Directory:

Tags:

International study shows that while British cancer survival has improved over the past 20 years the UK’s cancer survival rates lag behind the European average in 9 out of 10 cancers

10,000 cancer deaths could be prevented each year if the UK hit the European average

Analysis shows that some British cancer survival rates trail that of developing nations such as Jordan, Puerto Rico, Algeria and Ecuador

Since the inception of the NHS in 1948 policy makers and clinicians have viewed the problem as the NHS being under staffed and underfunded

But the answers to the cancer care challenge in the UK are not that straight forward

The world has changed and is changing while policy responses to challenges have remained static

UK cancer care lags that of other European nations: reasons and solutions Part 1

This Commentary is in 2 partsPart 1 focusses on cancer care in the UK, but much of its substance is relevant to other advanced nations with aging populations and large and escalating incidence rates and costs of cancer. Before drilling down into cancer care in Britain we briefly describe the etiology of cancer, the epidemiology of the condition as it relates to the UK and other wealthy nations, mention immunotherapy as indicative of evolving and significant new therapies, which give hope to cancer sufferers. We then describe the CONCORD-3 study reported in The Lancet in 2018. This is a highly regarded and significant international study, whose findings are widely recognised as the “gold standard” of comparative cancer care. It reports that although 5-year cancer survival rates (the internationally accepted indicator of cancer care) have improved in Britain over the past 2 decades, the UK is still trailing that of most large European countries. We conclude Part 1 with a brief description of UK initiatives to close its cancer-gap with other European countries.

Part 2, which will be published in 2 weeks, is an analysis of the cancer-gap between Britain and other European countries. We suggest that for decades, healthcare providers, policy makers and leading clinicians have suggested that the UK cancer-care gap is because of the lack of funding and the lack of healthcare professionals. Since the inception of the NHS in 1948 a policy mantra of “more” has taken root among policy makers, providers and clinicians: predominantly, “more money”, “more staff”, and “the government should do more”. We suggest that, over the lifetime of NHS England, a combination of Britain’s economic growth, its historical ties with Commonwealth countries and, since 1973, the reduction of barriers to the flow of labour between European countries, has given UK policy makers a convenient “get-out-of-jail-card” because they could always provide more money and more staff. Over the past 2 decades, this option has become less and less effective because of a combination of the slowdown of world economic growth, the rise of emerging economies such as India, and more recently Brexit.

We conclude with some thoughts about why a significant cancer care gap has opened between the UK and other European nations, and briefly describe some UK initiatives to close the gap. We suggest that the world has changed quicker than the thinking of policy makers and quicker than structural changes in the UK’s healthcare system. Improving cancer care in the Britain will require more than inertia projects. It will require more innovation, more long-term planning, more courage from policy makers, more focus on actual patients’ needs rather than what we are simply able to provide. Since 1948, the healthcare baton in the UK has been with an establishment comprised of policy makers, providers and leading clinicians. Over the past 70 years this establishment has become increasingly entrenched in past and narrow policy solutions. It has failed because the world has changed while It has remained static. It is time that the healthcare baton is passed to people with less self-interest at stake, who are less wedded to the past, and understand the new and rapidly evolving global healthcare ecosystem.

The UK’s cancer challenge

While British policy makers and health providers appear keen to stress that trends in the 5-year cancer survival rates (the internationally accepted measure for progress against cancer) have improved over the past 20 years, there is an element of “economy with the truth” in what they say. The UK is being left behind by significant advances in cancer survival rates in other nations. Treatment for 3.7m UK cancer patients diagnosed since 2000 is struggling to progress, especially for people diagnosed with brain, stomach and blood cancers. Further, your chances of dying after being diagnosed with prostate, pancreatic and lung cancer in Britain is significantly higher than in any other large European nation. This is according to CONCORD-3, the largest ever international cancer study reported in the January 2018 edition of the The Lancet.

The emperor of all maladies

Cancer is the uncontrolled proliferation of cells. In his 2010 Pulitzer Prize winning book, ‘The Emperor of All Maladies’, Siddhartha Mukherjee, professor of oncology at Columbia University Medical School in New York describes cancer cells as, "bloated and grotesque, with a dilated nucleus and a thin rim of cytoplasm, the sign of a cell whose very soul has been co-opted to divide and to keep dividing with pathological, monomaniacal purpose." Cancer occurs when a cell starts to divide repeatedly, producing abnormal copies of itself, rather than dividing occasionally just to replace worn out cells. If the immune system fails to destroy these cells, they continue to reproduce and invade and destroy surrounding healthy tissue. A number of forces can trigger these cell divisions, such as certain chemicals (carcinogens), chronic inflammation, hormones, lack of exercise, obesity, radiation, smoking, and viruses. ‘The emperor of all maladies’ is not just one disease. There are over 200 different types of cancer, each with its own methods of diagnosis and treatment. Most cancers are named after the organ or type of cell in which they start: for example, cancer that begins in the breast is called breast cancer. Cancer sometimes begins in one part of the body and can spread to other parts of the body through the blood and lymph systems This process is known as metastasis.

A practitioners’ views

According to Whitfield Growdon, an oncological surgeon at the Massachusetts General Hospital and Professor of Obstetrics, Gynaecology and Reproductive Biology at the Harvard University Medical School, “Cancer isa complicated set of events, which can happen in any cell in your body. Your body is comprised of tiny cells, which have the ability to grow, stop growing and to re-model, which is necessary to do all the functions that are required for living. But every cell in nature has the potential to lose control of its growth. It is this uncontrolled growth of an individual cell, which we call cancer. Cells can grow, they can spread, and if the cell growth is uncontrolled it can invade other tissues, which can lead to you losing the ability to perform vital functions that are required for your life,” see video below:

Epidemiology

There is scarcely a family in the developed world unaffected by cancer. But, this has not always been the case. Cancer only became a leading cause of death when we began to live long enough to get it. In 1911, the prevalence of cancer was low compared to what it is today. Then life expectancy in the UK was 51.5 and 52.2 years for males and females respectively. Similarly, in the US, at the beginning of the 20th century, life expectancy at birth was 47.3 years. Today, the median life expectancy in the UK is 81.6 and in the US 78.7. Significantly, the age at diagnosis for prostate cancer today is 67 and 61 for breast cancer. Approximately 12% of the UK population are aged 70 and above and account for 50.2% of the total cancers registered in 2014. 87% of all cancers in the US are diagnosed in people over 50.

Late diagnoses

Every 2 minutes in Britain someone is diagnosed with cancer, and almost 50% of these are diagnosed at a late stage. Every year in the UK there are more than 360,000 new cancer cases, which equates to nearly 990 newly diagnosed cancers every day. Taking a closer look at the UK data, we notice that since the early 1990s, incidence rates for all cancers combined have increased by 12%. The increase is larger in females than males. Over the past decade, incidence rates for all cancers combined have increased by 7%, with a larger increase in females: 8% as opposed to 3% in males. Over the next 2 decades, incidence rates for all cancers combined in Britain are projected to rise by 2%. Incidence rates in the UK are lower than in most European nations in males, but higher in females.

In 2015, breast, prostate, lung and bowel cancers together account for some 53% of all new cancer cases in the UK. Over the past decade, thyroid and liver cancers have shown the fastest increases in incidence in both males and females. Incidence rates of melanoma, small intestine, and kidney cancers have also increased markedly in males over the past 10 years. Over the same period, Incidence rates of kidney, melanoma, and head and neck cancers have also increased markedly in females. Despite the rise in incidence rates, in recent years mortality rates from cancer in England and Wales have fallen. Between 1994 and 2013, mortality rates from cancer for males and females fell by 30% and 22% respectively.

New therapies: immunotherapy/biologics

What gives hope to people living with cancer is partly new and innovative therapies. Over the past few decades immunotherapy, also called biological therapy, is an evolving treatment, which has become a significant part of the management of certain cancers. Immunotherapy is any form of treatment that uses the body's natural abilities that constitute the immune system to fight infection and disease or to protect the body from some of the side effects of treatment. This may be achieved either by stimulating your own immune system to attack cancer cells specifically, or by giving your immune system components to boost your body’s immune system in a general way. Immunotherapy works better for some types of cancer than for others. It is used by itself for some cancers, but for others it seems to work better when used with other types of therapy.

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London, and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZeneca, UK, “Biological therapies are treatments gaining importance globally as we progress with the management of cancer. Understanding the biology of cancer has enabled us to understand the targets that go wrong in those cancers. We have successfully used many treatments that hit directly those cancer targets in order to inhibit or “switch-off” the cancers. These biological therapies either can be useful on their own or more commonly, combined with standard treatments such as chemotherapy, surgery and radiotherapy.” See video below:

Why is the CONCORD-3 study significant?

CONCORD-3 reported in a 2018 edition of The Lancet is an international scientific collaboration designed to monitor trends in the survival of cancer patients throughout the world, and involves 600 investigators in over 300 institutions in 71 countries. The study compares the overall effectiveness of health systems to provide care for 18 cancer types, which collectively represent 75% of all cancers diagnosed worldwide. The study is specifically designed to: (i) monitor trends in the survival rates of cancer patients world-wide to 2014, (ii) inform national and global policy on cancer control, and (iii) enable a comparative evaluation of the effectiveness of health systems in providing cancer care. The study is the third of its kind and supports the over-arching goal of the 2013 World Cancer Declaration, to achieve “major reductions in premature deaths from cancer, and improvements in quality of life and cancer survival”.

CONCORD’s evidence base

The evidence base of the CONCORD-3 study is significant and is predicated upon the clinical records of 37.5m patients diagnosed with cancer between 2000 and 2014. Data are provided in over 4,700 data sets by 322 population-based cancer registries from 71 countries and territories; 47 of which provided data with 100% population coverage. The analysis is centralised, based upon tight protocols and standardised quality controls, and employs cutting-edge methods. The 71 participating countries and territories are home to a combined population of 4.9bn (UN figures for 2014). This represents 67% of the world's population (7.3bn). The 322 participating cancer registries contributed data on all cancer patients diagnosed among their combined resident populations of almost 1bn people (989m), which is 20% of the combined population of those countries. CONCORD-3 contributes to the evidence base for global policy on cancer management and control.

CONCORD-3 data base drives national and global policies on cancer control

Despite the care taken of the data management processes, no study is perfect, and It is reasonable to assume that a study the size of CONCORD-3 will have weaknesses. Notwithstanding, the study is “best in class” and its results are comparable within the limits of data quality. The international trends in cancer patient survival reported in the study reflect the comparative effectiveness of health systems in managing cancer patients. The findings of CONCORD-3 form part of the evidence that drives national and international policies on cancer control. For example, the International Atomic Energy Agency use the findings in its campaign to highlight global inequalities in cancer survival. The Organisation for Economic Co-operation and Development(OEDC) use the results of CONCORD as indicators of the quality of healthcare in 48 countries in its Health at a Glance publications, and the European Union use the findings in its Country Health Profiles for EU Member States.

Overall cancer survival is improving

Overall findings of the CONCORD-3 study suggest that the prospects for cancer patients are improving throughout the world and survival rates are increasing for some lethal cancers. Several cancers show significant increases in 5-year survival, including breast (80% to 86%), prostate (82% to 89%), rectum (55% to 63%) and colon (52% to 60%); reflecting better cancer management. Notwithstanding, there are significant differences in cancer outcomes between nations.

UK has worse cancer survival rates compared with other European nations

Despite the fact that increasingly more people are surviving cancer, British adult cancer patients continue to have worse survival rates after 5 years compared to the European average in 9 out of 10 cancers. Research comparing 29 countries shows survival rates in Sweden are almost 33% higher than in the UK. For ovarian cancer, which affects 7,400 British women each year, the UK comes 45th out of 59, with only 36.2% sufferers surviving 5 years. Some countries achieve nearly double this survival rate. When the largest 5 European countries - Germany, France, Britain, Italy and Spain - were compared for the 3 most common cancers, Britain came bottom for 2 of them. Britain’s survival rates were worse than the other 4 European nations for lung and prostate cancer, and second worst for breast cancer. With regard to pancreatic cancer British patients had just a 6.8% chance of survival, compared to 7.7% in Spain, 8.6% in France, 9.2% in Italy and 10.7% in Germany. This puts the UK 47th out of the 56 countries that had full data for this cancer. Studies suggest 10,000 deaths could be prevented each year if the UK were to keep up with the European average. The UK only exceeds the European average in melanoma. See table below.

Takeaways

Here we have introduced and described the findings of CONCORD-3, which suggests the UK lags significantly other European nations with regard to cancer survival rates. This sets the scene for part 2 of this Commentary, which will briefly describe some of the UK’s cancer initiatives to reduce premature death from cancer and enhance the care of people living with the disorder. Much has been achieved and over the past 2 decades, cancer mortality rates in the UK have been significantly reduced. Notwithstanding, more innovative and effective policies, which address the actual needs of patients rather than provide “more money and more staff” will be required if the UK is to reduce the cancer-care gap.

China is no longer a low cost ‘copycat’ economy. Indeed, it has bold plans to become a preeminent global force in genomic engineering to prevent and manage devastating and costly diseases. Here we briefly describe aspects of China’s multibillion-dollar, government-backed initiative, to own and control significant capacity to transform genomic data into precision medicines. This is not only a ‘numbers’ game. China’s drive to achieve its life science ambitions is also advantaged by a different approach to ‘individualism’ and privacy compared to that of the US; and this could have far-reaching implications for future civilizations.

Uneven playing fieldGenomic engineering and precision medicine have the potential to revolutionize how we prevent and treat intractable diseases. Who owns the intellectual property associated with genomic engineering, and who first exploits it, will reap significant commercial benefits in the future. However, genomic technologies are not like any other. This is because genetically modifying human genomes could trigger genetic changes across future generations. Misuse of such technologies therefore could result in serious harm for individuals and their families. On the other hand, over regulation of genomic engineering could slow or even derail the prevention and treatment of devastating and costly diseases. Establishing a balance, which supports measures to mitigate misuse of genomic technologies while allowing the advancement of precision medicine is critical. However, this has proven difficult to establish internationally.

Chinese scientists have crossed an ethical lineChinese culture interprets individualism and privacy differently to American culture, and therefore China responds differently to certain ethical standards compared to the US and some other Western nations. Indeed, national differences were ignited in 2012 when Chinese researchers published their findings of the world’s first endeavors to modify the genomes of human embryos to confer genetic resistance to certain diseases. Because such modifications are heritable critics argued that the Chinese scientists crossed a significant ethical line, and this was the start of a “slippery slope”, which could eventually lead to the creation of a two-tiered society, with elite citizens genetically engineered to be smarter, healthier and to live longer, and an underclass of biologically run-of-the-mill human beings.

International code of conduct called for but not adhered to2 prominent scientific journals, Nature and Science, rejected the Chinese research papers reporting world-first scientific breakthroughs on ethical grounds. Subsequently, Nature published a note calling for a global moratorium on the genetic modification of human embryos, suggesting that there are “grave concerns” about the ethics and safety of the technology. 40 countries have banned genetically modifying human embryos. In 2016, a report from the UK’s Nuffield Councilon Bioethics stressed the importance of an internationally agreed ethical code of conduct before genomic engineering develops further.

In 2017 an influential US science advisory group formed by the National Academy of Sciences and the National Academy of Medicine gave ‘lukewarm’ support to the modification of human embryos to prevent, “serious diseases and disabilities” in cases only where there are no other “reasonable alternatives”. The French oppose genomic modification, the Dutch and the Swedes support it, and a recent Nature editorial suggested that the EU is, “habitually paralyzed whenever genetic modification is discussed”. In the meantime, clinical studies, which involve genomic engineering, are advancing at a pace in China.

With regard to genome testing, western human rights activists have warned that China is targeting vulnerable groups and minorities to help build vast genomic databases without appropriate protection for individuals. Those include migrant workers, political dissidents and ethnic or religious minorities such as the Muslim Uighurs in China's far western Xinjiang region. Xinjiang authorities are reported to have invested some US$10bn in advanced sequencing equipment to enhance the collection and indexing of these data.

Different national interpretations of ‘individualism’ ‘Individualism’, which is at the core of ethical considerations of genomic engineering, is challenging to define because of its different cultural, political and social interpretations. For example, following the French Revolution, individualisme was used pejoratively in France to signify the sources of social dissolution and anarchy, and the elevation of individual interests above those of the collective. The contemporary Chinese interpretation of individualism is similar to the early 19th century French interpretation. It does not stress a person’s uniqueness and separation from the State, but emphasizes an individual’s social; contract and harmony with the State. By contrast, American individualism is perceived as an inalienable natural right of all citizens, and independent of the State.

Further, American individuals are actively encouraged to challenge and influence the government and its regulatory bodies, whereas in China citizens are expected to unquestionably support the State. China is a one party state, where individuals generally accept that their government and its leaders represent their higher interests, and most citizens therefore accept the fact that they are not expected to challenge and influence policies determined by the State and its leaders. This difference provides China with a significant competitive advantage in its endeavors to become a world leader in the life sciences,

Human capital

By 2025, some 2bn human genomes could be sequenced. This not only presents ethical challenges, but also significant human capital challenges. The development of personalized medicines is predicated upon the ability to aggregate and process vast amounts of individual genomic, physiological, health, environmental and lifestyle data. This requires next generation sequencing technologies, smart AI systems, and advanced data managers of which there is a global shortage. Thus, the cultivation and recruitment of appropriate human capital is central to competing within the rapidly evolving international genomic engineering marketplace. The fact that China has a more efficacious strategy to achieve this than the US and other Western democracies provides it with another significant competitive advantage.

STEM graduatesSince the turn of the century, China has been engaged in a silent revolution to substantially increase its pool of graduates in science, technology, engineering and mathematics (STEM), while the pool of such graduates in the US and other Western democracies has been shrinking. In 2016, China was building the equivalent of almost one university a week, which has resulted in a significant shift in the world's population of STEM graduates. According to the World Economic Forum, in 2016, the number of people graduating in China and India were respectively 4.7m and 2.6m, while in the US only 568,000 graduated. In 2013, 40% of all Chinese graduates finished a degree in STEM, over twice the share of that in US universities. In 2016, India had the most graduates of any country worldwide with 78m, China followed closely with 77.7m, and the US came third with 67m graduates.

University education thriving in China and struggling in the WestIn addition to China being ahead of both the US and Europe in producing STEM graduates; the gap behind the top 2 countries and the US is widening. Projections suggest that by 2030 the number of 25 to 34-year-old graduates in China will increase by a further 300%, compared with an expected rise of around 30% in the US and Europe. In the US students have been struggling to afford university fees, and most European countries have put a brake on expanding their universities by either not making public investments or restricting universities to raise money themselves.

The increasing impact of Chinese life sciences China's rapid expansion in STEM graduates suggests that the future might be different to the past. Today, China has more graduate researchers than any other country, and it is rapidly catching up with the US in the number of scientific papers published. The first published papers to describe genetic modifications of human embryos came from Chinese scientists.

Further, according to the World Intellectual Property Organization, domestic patent applications inside China have soared from zero at the start of the 21st century to some 928,000 in 2014: 40% more than the US’s 579,000, and almost 3 times that of Japan’s 326,000.

China’s strategy to reverse the brain drainComplementing China’s prioritization of domestic STEM education is its “Qianren Jihua” (Thousand Talents) strategy. This, established in the wake of the 2008 global financial crisis to reverse China’s brain drain, trawls the world to seek and attract highly skilled human capital to China by offering them incentives. Qianren Jihua’s objective is to encourage STEM qualified Chinese ex patriots to return to China, and encourage those who already reside in China to stay, and together help create an internationally competitive university sector by increasing the production of world-class research to support China’s plans to dominate precision medicine and life sciences.

Government commitment

In 2016, China announced plans for a multi-billion dollar project to enhance its competitiveness by becoming a global leader in molecular science and genomics. China is committed to supporting at least three principal institutions, including the Beijing Genomics Institute (BGI), to sequence the genomes of many millions.

In addition to investments at home, China also is investing in centers similar to that of BGI abroad. Over the past 2 years China has invested more than US$110bn on technology M&A deals, which it justifies by suggesting that emerging technologies are, “the main battlefields of the economy”. Early in 2017 BGI announced the launch of a US Innovation Center, co-located in Seattle and San Jose. The Seattle organization is focused on precision medicine and includes collaborations with the University of Washington, the Allen Institute for Brain Science, and the Bill and Melinda Gates Foundation. The San Jose facility, where BGI already has a laboratory employing over 100, supports its ambitions to develop next-generation sequencing technologies, which until now have been dominated by the US sequencing company Illumina.

Changing structure of China’s economySome suggest that China’s rise on the world life sciences stage will be short lived because the nation is in the midst of a challenging transition to a slower-growing, consumption-driven economy, and therefore will not be able to sustain such levels of investment; and this will dent its ambition to become a global player in genomic science. An alternative argument suggests slower growth forces China to act smarter, and this is what drives its precision medicine ambitions.

Between 1985 and 2015, China’s annual GDP rose, on average, by 9.4%. Fuelling this growth was a steady supply of workers entering the labour force and massive government led infrastructure investments. Now, because of China’s ageing population, its labour capacity has peaked and started to decline. Without labour force expansion, and investment constrained by debt, China is obliged to rely more heavily on innovation to improve its productivity. And this drives, rather than slows, China’s strategy to become a world leader in genomic technologies and personalized medicine.

China’s economic growth is slowing, but its production of scientific research is growingAlthough China’s economy is slowing, it is still comparatively large. In 2000, China spent as much on R&D as France; now it invests more in genomics than the EU, when adjusted for the purchasing power of its currency. Today, China produces more research articles than any other nation, apart from the US, and its authors’ feature on around 20% of the world’s most-cited peer reviewed papers. Top Chinese scientific institutions are breaking into lists of the world’s best, and the nation has created some unparalleled research facilities. Even now, every 16 weeks China produces a Greece-size economy, and doubles the entire size of its economy every 7 years. Today, China has an economy similar in size to that of the US, and most projections suggest that, over the next 2 decades, China’s economy will dwarf that of the US.

Takeaways

China is cloning its successful strategy to own and control significant mineral and mining rights to the life sciences. Over the past 20 years China has actively pursued mining deals in different global geographies, and now controls significant mining rights and mineral assets in Africa and a few other countries. This allows China to affect the aggregate supply and world market prices of certain natural resources. Now, China is cloning this commercially successful strategy to the life sciences, and has empowered and encouraged a number of state owned and private companies to own and control genomic engineering and precision medicine. China’s single-minded determination to become a world leader in life sciences, and its interpretation of individualism and privacy issues could have far reaching implications for the future of humanity.

Professor Dame Sally Davies, England’s Chief Medical Officer, is right. (Genomics) “has the potential to change medicine forever. . . . The age of precision medicine is now, and the NHS must act fast to keep its place at the forefront of global science.”

It is doubtful whether the UK will be able to maintain its place as a global frontrunner in genomics and personalized medicine. It is even doubtful whether the US, the first nation to discover the genome, and which became preeminent in genomic research, will be able to maintain its position. China, with its well-funded strategy to become the world’s leader in genomics and targeted therapies, is likely to usurp the UK and the US in the next decade.

This Commentary is in 2 parts. Part 1 provides a brief description of the global scientific competition between nation states to turn genomic data into medical benefits. China’s rise, which is described, could have significant implications for the future ownership of medical innovations, data protection, and bio-security. Part 2, which follows in 2 weeks, describes some of the ethical, privacy, human capital and economic challenges associated with transforming genomic data into effective personal therapies.

Turning genomic data into medical benefits

Turning genomic data into medical benefits is very demanding. It requires a committed government willing and able to spend billions, a deep understanding of the relationship between genes and physiological traits, next generation sequencing technologies, artificial intelligence (AI) systems to identify patterns in petabytes (1 petabyte is equivalent to 1m gigabytes) of complex data, world-class bio-informaticians, who are in short supply; comprehensive and sophisticated bio depositories, a living bio bank, a secure data center, digitization synthesis and editing platforms, and petabytes of both genomic, clinical, and personal data. Before describing how the UK, US and China are endeavoring to transform genomic data into personal medicine, let us refresh our understanding of genomics.

Genomics, the Human Genomic Project and epigenetics

It is widely understood that your genes are responsible for passing specific features or diseases from one generation to the next via DNA, and genetics is the study of the way this is done. However, it is less widely known that your genes are influenced by environmental and other factors. Scientists have demonstrated that inherited genes are not static, and lifestyles and environmental factors can precipitate a chemical reaction within your body that could permanently alter the way your genes react. This environmentally triggered gene expression, or epigenetic imprint, can be bad, such as a disease; or good, such as a tolerant predisposition. Epigenetics is still developing as an area of research, but it has demonstrated that preventing and managing disease is as much to do with lifestyles and the environment, as it is to do with inherited genes and drugs. If environmental exposure can trigger a chemical change in your genes that results in the onset of disease, then scientists might be able to pharmacologically manipulate the same mechanisms in order to reverse the disease.

DNA is constantly subject to mutations, which can lead to missing or malformed proteins, and that can lead to disease. You all start your lives with some mutations, which are inherited from your parents, and are called germ-line mutations. However, you can also acquire mutations during your lifetime. Some happen during cell division, when DNA gets duplicated, other mutations are caused when environmental factors including, UV radiation, chemicals, and viruses damage DNA.

You have a complete set of genes in almost every healthy cell in your body. One set of all these genes, (plus the DNA between them), is called a genome. The genome is the collection of 20,000 genes, including 3.2bn letters of DNA, which make up an individual. We all share about 99.8% of the genome. The secrets of your individuality, and also of the diseases you are prone to, lie in the other 0.2%, which is about 3 or 4m letters of DNA. The genome is known as ‘the blueprint’ of life’, and genomics is the study of the whole genome, and how it works. Whole genome sequencing (WGS) is the process of determining the complete DNA sequence of an organism's genome at a point in time.

‘The Human Genome Project’ officially began in 1990 as an international research effort to determine a complete and accurate sequence of the 3bn DNA base pairs, which make up the human genome, and to find all of the estimated 20 to 25,000 human genes. The project was completed in April 2003. This first sequencing of the human genome took 13 years and cost some US$3bn. Today, it takes a couple of days to sequence a genome, and costs range from US$260 for targeted sequencing to some US$4,000 for WGS. Despite the rapidly improving capacity to read, sequence and edit the information contained in the human genome, we still do not understand most of the genome’s functions and how they impact our physiology and health.

Roger Kornberg explains the importance of genomics

Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry, explains the significance of sequencing the human genome, “The determination of the human genome sequence and the associated activity called genomics; and the purposes for which they may be put for medical uses, takes several forms. The knowledge of the sequence enables us to identify every component of the body responsible for all of the processes of life. In particular, to identify any component that is either defective or whose activity we may adjust to address a problem or a condition. So the human genome sequence makes available to us the entire array of potential targets for drug development. . . . . The second way in which the sequence and the associated science of genomics play an important role is in regard to individual variations. Not every human genome sequence is the same. There is a wide variation, which in the first instance is manifest in our different appearances and capabilities. But it goes far deeper because it is also reflected in our different responses to invasion by microorganisms, to the development of cancer and to our susceptibility to disease in general. It will ultimately be possible, by analyzing individual genome sequences to construct a profile of such susceptibilities for every individual, a profile of the response to pharmaceuticals for every individual, and thus to tailor medicines to the needs of individuals.” See video below.

UK’s endeavors to transform genomic data into personal therapies

In 2013 the UK government set up Genomics England, a company charged with sequencing 100,000 whole genomes by 2017. In 2014, the government announced a £78m deal with Illumina, a US sequencing company, to provide Genomics England with next generation whole genome sequencing services. At the same time the Wellcome Trust invested £27m in a state-of-the-art sequencing hub to enable Genomics England to become part of the Wellcome Trust’s Genome Campus in Hinxton, near Cambridge, England. In 2015, the UK government pledged £215m to Genomics England.

DNA testing and cancer“DNA sequencing is simply the process of reading the code that is in any organism . . . It’s essentially a technology that allows us to extract DNA from a cell, or many cells, pass it through a sophisticated machine and read out the sequence for that organism or individual,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia; see video below. “DNA testing has becomeincreasingly widespread because advances in technology have made the opportunity to sequence the DNA of individuals affordable and rapid . . . DNA testing in the context of cancer can be useful to identify a genetic risk of cancer, and to help clinicians make therapeutic decisions for someone who has cancer,” says Bowtell, see video below.

What is DNA sequencing?

What are the advanteges of a person having a DNA test?

Need for National Genome BoardDespite significant investments by the UK government, Professor Davies, England’s Chief Medical Officer, complained in her 2017 Annual Report that genomic testing in the UK is like a “cottage industry” and recommended setting up a new National Genome Board tasked with making whole genome sequencing (WGS) standard practice in the NHS across cancer care, as well as some other areas of medicine, within the next 5 years.

USA’s endeavors to transform genomic data into personal therapies

In early 2015 President Obama announced plans to launch a $215m public-private precision medicine initiative, which involved the health records and DNA of 1m people, to leverage advances in genomics with the intention of accelerating biomedical discoveries in the hope of yielding more personalized medical treatments for patients. A White House spokesperson described this as “a game changer that holds the potential to revolutionize how we approach health in the US and around the world.”

Data management challengesThe American plan did not seek to create a single bio-bank, but instead chose a distributive approach that combines data from over 200 large on-going health studies, which together involves some 2m people. The ability of computer systems or software to exchange and make use of information stored in such diverse medical records, and numerous gene databases presents a significant challenge for the US plan. According to Bowtell, “Data sharing is widespreadin an ethically appropriate way between research institutions and clinical groups. The main obstacles to more effective sharing of information are the very substantial informatics challenges. Often health systems have their own particular ways of coding information, which are not cross compatible between different jurisdictions. Hospitals are limited in their ability to capture information because it takes time and effort. Often information that could be useful to researchers, and ultimately to patients, is lost, just because the data are not being systematically collected.” See video below.

China’s endeavors to transform genomic data into personal therapies

In 2016, the Chinese government launched a US$9bn-15-year endeavor aimed at turning China into a global scientific leader by harnessing computing and AI technologies for interpreting genomic and health data. This positions China to eclipse similar UK and US initiatives.

Virtuous circleTransforming genomic data to medical therapies is more than a numbers race. Chinese scientists are gaining access to ever growing amounts of human genomic data, and developing the machine-learning capabilities required to transform these data into sophisticated diagnostics and therapeutics, which are expected to drive the economy of the future. The more genomic data a nation has the better its potential clinical outcomes. The better a nation’s clinical outcomes the more data a nation can collect. The more data a nation collects the more talent a nation attracts. The more talent a nation attracts the better its clinical outcomes.

TheBeijing Genomics InstituteIn 2010 China became the global leader in DNA sequencing because of one company: the Beijing Genomics Institute (BGI), which was created in 1999 as a non-governmental independent research institute, then affiliated to the Chinese Academy of Sciences, in order to participate in the Human Genome Project as China's representative. In 2010, BGI received US$1.5bn from the China Development Bank, and established branches in the US and Europe. In 2011 BGI employed 4,000 scientists and technicians. While BGI has had a chequered history, today it is one of the world’s most comprehensive and sophisticated bio depositories.

The China National GeneBankIn 2016 BGI-Shenzhen established the China National GeneBank (CNGB) on a 47,500sq.m site. This is the first national gene bank to integrate a large-scale bio-repository and a genomic database, with a goal of enabling breakthroughs in human health research. The gene-bank is supported by BGI’s high-throughput sequencing and bio-informatics capacity, and will not only provide a repository for biological collection, but more importantly, it is expected to develop a novel platform to further understand genomic mechanisms of life. During the first phase of its development the CNGB will have saved more than 10m bio-samples, and have storage capacity for 20 petabytes (20m gigabytes) of data, which are expected to increase to 500 petabytes in the second phase of its development. The CNGB represents the new generation of a genetic resource repository, bioinformatics database, knowledge database and a tool library, “to systematically store, read, understand, write, and apply genetic data,” says Mei Yonghong, its Director.

Whole-genome sequencing for $100The CNGB could also help to bring down the cost of genomic sequencing. It is currently possible to sequence an individual's entire genome for under US$1,000, but the CNGB aims to reduce the price to US$152. Meanwhile, researchers at Complete Genomics, a US company acquired by BGI in 2013, which has developed and commercialized a DNA sequencing platform for human genome sequencing and analysis, are pushing the technology further to enable whole-genome sequencing for US$100 per sample. China's share of the world's sequencing-capacity is estimated to be between 20% and 30%, which is lower than when BGI was in its heyday, but expected to increase fast. “Sequencing capacity is rising rapidly everywhere, but it's rising more rapidly in China than anywhere else,” says Richard Daly, CEO, DNAnexus, a US company, which supplies cloud platforms for large-scale genomics data.

The intersection of genomics and AI Making sense of 1m human genomes is a major challenge, says Professor Jian Wang, former BGI President and co-founder, who has started another company called iCarbonX. Also based in Shenzhen, the company is at the intersection of genomics and AI. iCarbonX has raised more than US$600m, and plans to collect genomic data from more than 1m people, and complement these data with other biological information including changes in levels of proteins and metabolites. This is expected to allow iCarbonX to develop a new digital ecosystem, comprised of billions of connections between huge amounts of individuals’ biological, medical, behavioural and psychological data in order to understand how their genes interact and mutate, how diseases and aging manifest themselves in cells over time, how everyday lifestyle choices affect morbidity, and how these personal susceptibilities play a role in a wide range of treatments.

iCarbonX is expected to gather data from brain imaging, biosensors, and smart toilets, which will allow real-time monitoring of urine and faeces. The Company’s goal is to be able to study the evolution of our genome as we age and design personalized health predictions such as susceptibilities to diseases and tailored treatment options. iCarbonX’s endeavours are expected to dwarf efforts by other US Internet giants at the intersection of genomics and AI.

Ethical challenges

China’s single-minded objective to turn its knowhow and experience of genome sequencing into personal targeted medical therapies has made it a significant global competitive force in life sciences. However, precision medicine’s potential to revolutionize advances in how we treat diseases confers on it moral and ethical obligations. For personal therapies to be effective, it is important that genomic data are complemented with clinical and other personal data. This combination of data is as personal as personal information gets. There could be potential harm to the tested individual and family if genomic information from testing is misused. Reconciling therapy and privacy is important, because privacy issues concerning patients' genomic data can slow or derail the progression of novel personal therapies to prevent and manage intractable diseases. The stakes are high in terms of biosecurity, as genomic research is both therapeutic and a strategic element of national security. While it is crucial to leverage genomic data for future health, economic and biodefense capital, these data will also have to be appropriately managed and protected. Part 2 of this Commentary dives into these challenges a little deeper, and describes some of China’s competitive advantages in the race to become the world’s preeminent nation in genomics and precision medicine.

Takeaways

Despite the endeavours of the UK and US to remain at the forefront of the international competition to transform genomic data into personalized medical therapies for some of the worlds most common and intractable diseases, it seems reasonable to assume that China is on the cusp of becoming the most dominant nation in novel personalized treatments. Notwithstanding, China’s determination to assume the global frontrunner position in genomic science might have blunted its concerns for some of the ethical issues, which surround the life sciences. To the extent that this might be the case the future of humanity might well differ significantly from the generally accepted western vision.

Directory:

Tags:

A number of new studies on ovarian cancer show “promising” results for patients who develop chemo-resistance

A Dutch study uses conventional chemotherapeutics more intensively

Another study uses a new class of drug discovered by the UK’s Institute of Cancer Research

Genetic testing is playing an increasing role in the reduction of chemo-resistance

Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients

The UK’s Chief Medical Officer suggests that whole genome sequencing should become standard practice on the NHS across cancer care

A new class of chemotherapeutic agent is directed at targeting cancers with defective DNA-damage repair

Improvements in cancer care have been both scientific and organizational

Utilizing and sequencing the treatment options for ovarian cancer may have a significant impact on the overall survival rates of patients

Multidisciplinary teams are transforming ovarian cancer care

Improving ovarian cancer treatment

Part II

Part-1 described ovarian cancer, the difficulties of diagnosing the disease early, and the challenges of developing effective screening mechanisms for it in pre-symptomatic women. Here, in part-2, we report new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.

1

Established chemotherapy agents combined and used intensively

The first study we describe is Dutch, published in 2017 in the British Journal of Cancer. It reports findings of a pioneering type of intensive chemotherapy, which was effective in 80% of patients with advanced ovarian cancer and whose first line of chemotherapy had failed. Currently, such patients have few options because more than 50% do not respond to follow-up chemotherapy.

Intensive combinations

The study, led by Dr. Ronald de Wit, of the Rotterdam Cancer Institute, involved 98 patients who first responded to chemotherapy only later to relapse. Patients in the study were divided into three groups according to the severity of their condition, and treated with a combination of two well established chemotherapy agents: cisplatin and etopside, but the new treatment used the drugs much more intensively than usual.

Usually, chemotherapy is delivered as a course of a number of 21-day sessions (cycles) over several months. Between cycles patients are given time to recover from the toxic side effects, including neurotoxicity, nephrotoxicity, ototoxicity, and chemotherapy-induced nausea and vomiting (CINV). In de Wit’s study the combined chemotherapy drugs were given intensively, on a weekly basis, along with drugs to prevent adverse side effects.

Findings

Among the group of women in de Wit’s study who were most seriously ill, 46% responded to the new treatment, compared with less than 15% for current therapies. The response rates of the two groups of women who were least ill to the new treatment were 92% and 91%. This compares to responses of 50% and 20 to 30% with standard therapies. Overall, 80% of the women's tumours shrank, and 43% showed a complete response, with all signs of their cancers disappearing.

Immediate benefit

"We were delighted by the success of the study. The new drug combination was highly effective at keeping women alive for longer, giving real hope to those who would otherwise have had very little . . . . We were worried the women would be too ill to cope with the treatment, but in fact, they suffered relatively few side effects. And since these drugs are readily available, there's no reason why women shouldn't start to benefit from them right away," says de Wit.

2

ONX-0801 study

The second study we report was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting in Chicago. It describes findings of an experimental new treatment that was found to dramatically shrink advanced ovarian cancer tumors, which researchers suggest is, “much more than anything that has been achieved in the last 10 years”.

“Very promising” findings

Dr. Udai Banerji, the leader of the study, is the Deputy Director of Drug Development at the UK’s Institute of Cancer Research (ICR). Banerji and his team were testing a drug, known as ONX-0801, for safety, but found that tumors, in half of the 15 women studied, shrank during the trial. A response Banerji called, “highly unusual”, and “very promising”. The drug, which is, “a completely new mechanism of action,” could add, “upward of six months to the lives of patients with minimal side effects”. If further clinical studies prove the drug’s effectiveness, it could potentially be used in early-stage ovarian cancer where, “the impact on survival may be better,” says Banerji.

New class of drug

ONX-0801 is the first in a new class of drug discovered by the ICR, and tested with the Royal Marsden NHS Foundation Trust. It attacks ovarian cancer by mimicking folic acid in order to enter the cancer cells. The drug then kills these cells by blocking a molecule called thymidylate synthase. ONX-0801 could be effective in treating the large group of chemo-resistant sufferers for whom there are currently limited options. Additionally, because the new therapy targets cancer cells and does not affect surrounding healthy cells, there are fewer side effects. Further, experts have developed tests to detect the cells that respond positively to this new treatment, which means oncologists can identify those women who are likely to benefit from the therapy the most.

Cautious note

Although the study is said to be “very promising”, Michel Coleman, Professor of Epidemiology at the London School of Hygiene & Tropical Medicine, suggests caution in interpreting its findings as it is such a small study and while, “shrinkage of tumors is important . . . it is not the same as producing the hoped-for extension of survival for women with ovarian cancer.”

3

Genetic testing

Resistance to chemotherapy can be reduced by DNA testing to obtain an increased knowledge of the molecular mechanisms of ovarian cancer pathogenesis, which facilitate personalized therapies that target certain subtypes of the disease. “Some people choose to have DNA testing because either they have developed cancer or family members have,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia. “In the context of cancer, personalized medicine is the concept that we look into the cancer cell and understand for that person what specific genetic changes have occurred in their cancer. Based on those specific changes, for that person we then decide on a type of therapy, which is most appropriate for the genetic changes that have occurred in that cancer . . . . . Typically this involves taking a sample of the cancer, running it through DNA sequencing machines, and using bioinformatics to interpret the information. Then, the results, which include gene mutations need to be interpreted by a multidisciplinary team, in order to decide the best possible treatment options for that particular patient,” says Bowtell: see videos below..

How do genetic mutations translate into personalised medicine?

How is personalised medicine implemented?

Mainstreaming cancer geneticsSince 2014 the Royal Marsden NHS Trust Hospital in Londonhas employed genetic profiling of ovarian cancer patients, and have used laboratories with enhanced genetic testing capabilities to streamline and speed up processing time, lower costs, and help meet the large and growing demand for rapid, accurate and affordable genetic testing. The program called, Mainstreaming Cancer Genetics, helps women cancer patients make critical decisions about their treatment options. Currently, fewer than 33% of patients are tested, but this study spearheaded the beginning of a significant change. In her 2017 Annual Report, Professor Dame Sally Davies, England’s Chief Medical Office suggested that within the next 5 years all cancer patients should be routinely offered DNA tests on the NHS to help them select the best personalized treatments.

Bringing genetic testing to patientsAccording to Nazneen Rahman, Professor and Head of the Division of Genetics and Epidemiology at the ICR, and Head of the Cancer Genetics Unit at the Royal Marsden Hospital, London, “There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex . . . . We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital.”

More people benefiting from affordable rapid advanced genetic testingTreatment strategies that improve the selectivity of current chemotherapy have the potential to make a dramatic impact on ovarian cancer patient outcomes. The Marsden is now offering genetic tests to three times more cancer patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.” If the UK government acts on the recommendations of Davies, there could be a national center for genetic testing within the next 5 years.

4

PARP Inhibitors and personalized therapy

Since 2 seminal 2005 publications in Nature, (Bryant et al, 2005; and Farmer et al, 2005) which reported the extremely high sensitivity of BRCA mutant cell lines to the enzyme poly (ADP-ribose) polymerase (PARP) inhibition, there has been a scientific race to exploit a new class of cancer drug called PARP inhibitors. The family of PARP inhibitors represents a widely researched and promising alternative for the targeted therapy of ovarian malignancies. Over the past few years, PARP inhibitors have successfully moved into clinical practice, and are now used to help improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.Recent (PARP) approvalsIn 2014, olaparib was the first PARP inhibitor to obtain EU approval as a treatment for ovarian cancer patients who had become resistant to platinum-based chemotherapy. In 2017, the FDA granted the drug ‘priority review’ as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer while confirmatory studies are completed. In December 2016, the FDA granted ‘accelerated approval’ for rucaparib, another (PARP) inhibitor for the treatment of women with advanced ovarian cancers who have been treated with two or more chemotherapies, and whose tumors have specific BRCA gene mutations.

Early in 2017, the drug niraparib was the first PARP inhibitor to be approved by the FDA for the maintenance treatment of adult patients with recurrent gynaecological cancers who are resistant to platinum-based chemotherapy. The approval was based upon data from an international randomized, prospectively designed phase III clinical study, which enrolled 553 patients, and showed a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. In conjunction with the accelerated 2017 FDA approval for rucaparib, the FDA also approved a BRCA diagnostic test, which identifies patients with advanced ovarian cancer eligible for treatment with rucaparib.

New class of chemotherapiesPARP inhibitors may represent a potentially significant new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. Currently, these drugs have a palliative indication for a relatively small cohort of patients. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clearer understanding of the mechanism of action, and a better understanding of their toxicity profile will be required. Once this is achieved PARP inhibitors could to be employed in the curative, rather than the palliative setting.

5

The future of cancer care and multidisciplinary teams

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit, we now have “many options” for treating ovarian cancer. However, “how we utilize and sequence these options may have a significant impact on the overall survival of a patient. Better understanding of the disease through science is constantly turning up new options. For the first time in the last 5 years we are developing options in real time for patients. Patients almost are able to benefit from these options as they are relapsing from their disease. Keeping patients alive for longer allows them to access new treatments . . . It’s truly remarkable to see this in real time as a doctor,” says Gabra: see video.

A significant number of mostly private patients diagnosed with ovarian cancer draw comfort from the belief that they, “have the best oncologist”. This view fails to grasp the challenges facing individual clinicians acting on their own to treat a devilishly complex disease such as ovarian cancer. “The main improvements in cancer care have been organizational and scientific.” says Gabra. “It is not enough to create new science and new treatments. It is also important to rigorously implement these. The most effective way to do this is via a ‘tumor board’ or a ‘multidisciplinary clinic or team’, where various specialists such as surgeons, radiotherapists, medical oncologists, pathologists, clinical nurse specialists, etc come together and discuss each individual patient. Such multidisciplinary discussion results in the best utilizations of currently available treatment options in the right sequence. It’s difficult to do this for a doctor acting on his or her own and making isolated decisions . . . Multidisciplinary decision-making has transformed cancer care,” says Gabra: see video.

Takeaways

This Commentary provides a flavor of some of the recent advances in ovarian cancer research and care, and suggests that treatment options have improved in the 4 years since Maurice Saatchi described ovarian cancer care as, “degrading, medieval and ineffective” leading “only to death”. However, it is worth stressing that care is both organizational and scientific, and multidisciplinary teams can transform care and prolong life.

Directory:

Tags:

Ovarian cancer is a deadly disease that is challenging to diagnose and manage

Although it only accounts for 3% of cancers in women, it is the 5th leading cause of cancer death among women

If diagnosed and treated early before it spreads the 5-year survival rate is 92%

But only 15% of women with ovarian cancer are diagnosed early

The disease is hard to diagnose because it is rare, the symptoms are relatively benign, and there is no effective screening

Ovarian cancer is not one disease, but a collection of subtypes each demanding specific treatment pathways

Gold standard treatment is surgery followed by chemotherapy

A large proportion of patients develop resistance to chemotherapy

Improving ovarian cancer treatment

Part I

Are things beginning to improve for people living with ovarian cancer? When the British advertising magnate Lord Maurice Saatchi’s wife died of ovarian cancer in 2012 he described her treatment as, “degrading, medieval and ineffective” leading “only to death”. Ovarian cancer patients have long had limited treatment options, which have not changed much in the past two decades, but recently things have begun to change.

In this Commentary

This is the first of a 2-part Commentary on ovarian cancer, which briefly describes the condition, explains the difficulties of diagnosing it early, and discusses some of the challenges of developing effective screening mechanisms for the cancer in pre-symptomatic women. Part 2, which will follow separately next week, reports new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. It also suggests that improvements in ovarian cancer care are both organizational and scientific. Experts believe that they now have a number of treatment options available to them. Utilising and sequencing these appropriately can have a significant impact on the overall survival rates of patients.Multidisciplinary teams, which are not universally available to all ovarian cancer patients, bring together all specialisms involved in the therapeutic pathway to consider and suggest optimal treatment steps for individual patients, and make a significant contribution to improved ovarian cancer care. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.

Ovarian cancer: a complex and deadly disease

The ovaries are a pair of small organs located low in the stomach that are connected to the womb and store a woman’s supply of eggs. Ovarian cancer is driven by multicellular pathways, and is better understood as a collection of subtypes with changing origins and clinical behaviors, rather than as a single disease. The tumors often have heterogeneous cell populations, which form unique microcellular environments. The prevalence of ovarian cancer among gynecological malignancies is rising, and is one the most deadly and hard to treat malignancies. While the disease only accounts for about 3% of cancers in women, it is one of the most common types of cancer in women, the 5th leading cause of cancer-related death among women, and the deadliest of gynecologic cancers. The risk of ovarian cancer increases with age. It is rare in women younger than 40, most ovarian cancers develop after menopause. 50% of all ovarian cancers are found in women 63 or older.According to the American Cancer Society the five-year survival rate for all ovarian cancers is 45%. Most women are diagnosed with late-stage ovarian disease and, the 5-year survival rates for these patients are roughly 30%. Age adjusted survival rates of ovarian cancer are improving in most developed countries. For instance, between 1970 and 2010, the 10-year survival rates for ovarian cancer in England increased by 16%, and the 5-year survival rates have almost doubled.This is because of the favorable trends in the use of oral contraceptives, which were introduced early in developed countries. Declines in menopausal hormone use may also have had a favorable effect in older women as well as improved diagnosis, management and therapies. According to Public Health England, over the past 20 years the incidence of ovarian cancer in England has remained fairly stable, although it has decreased slightly in the last few years. Between 2008 and 2010 in England, 36% of some 14,000 women diagnosed with ovarian cancer died in the first year, and more than 1,600 died in the first month. There were 7,378 new cases of ovarian cancer in the UK in 2014 and more than 4,000 women died from the disease.

Benign symptoms difficult to diagnose

If ovarian cancer is diagnosed and treated early before it spreads from the ovaries to the abdomen, the 5-year relative survival rate is 92%. However, only 15% of all ovarian cancers are found at this early stage. This is because it is hard to diagnose since the disease is so rare, the symptoms are relatively benign, and there is no effective screening. As a result, the illness tends not to be detected until the latter stages in around 60% of women, when the prognosis is poor. In about 20% of cases the disease is not diagnosed until it is incurable. Feeling bloated most days for three weeks or more is a significant sign of ovarian cancer. Other symptoms include: feeling full quickly, loss of appetite, pelvic or stomach pain, needing to urinate more frequently than normal, changes in bowel habit, feeling very tired, and unexplained weight loss.

“Tumors go from the earliest stage 1 directly to stage 3”

In the video below Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit says, “Ovarian cancer is often diagnosed latebecause in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers, the notion that ovarian cancer progresses from stage 1 to stage 2, to stage 3 is possibly mythological. The reality is, these cancer cells often commence in the fallopian tube with a very small primary tumor, which disseminates directly into the peritoneal cavity. In other words, the tumors go from the earliest of stage 1 directly to stage 3."

Ovarian cancer screening and CA-125

For years scientists have been searching for an effective screening test for ovarian cancer in pre-symptomtic women. The 2 most common are transvaginal ultrasound (TVUS) and the CA-125 blood test. The former uses sound waves to examine the uterus, fallopian tubes, and ovaries by putting an ultrasound wand into the vagina. It can help find a tumor in the ovary, but cannot tell if the tumor is cancerous or benign. Most tumors identified by TVUS are not cancerous. So far, the most promising screening method is CA-125, which measures a protein antigen produced by the tumor.

CA-125 studies

To-date, 2 large ovarian cancer screening studies have been completed: one in the US, and another in the UK. Both looked at using the CA-125 blood test along with TVUS to detect ovarian cancer. In these studies, more cancers were found in the women who were screened, and some were at an early stage. But the outcomes of the women who were screened were no better than the women who were not screened: the screened women did not live longer and were not less likely to die from ovarian cancer.

Another study published in 2017 in the Journal of Clinical Oncology screened 4,346 women over 3 years at 42 centers across the UK, undertook follow-up studies 5 years later, and came to similar conclusions as the 2 previous studies. Further, “there are a number of non-ovarian diseases, which can cause elevated CA-125’s. Breast cancer, endometriosis, and irritation of the peritoneal cavity can all cause elevated CA-125,” says Michael Birrer, Director of Medical Gynecologic Oncology at the Massachusetts General Hospital and Professor of Medicine at Harvard University.

Controversial findings Findings from screening tests using CA-125 can give false positives for ovarian cancer, and this puts pressure on patients to have further, often unnecessary interventions, which sometimes include surgery. Also, the limitations of the CA-125 test mean that many women with early stage ovarian cancer will receive a false negative from testing, and not get further treatment for their condition. Thus, the potential role of CA-125 for the early detection of ovarian cancer is controversial, and therefore it has not been adopted for widespread screening in asymptomatic women.

In the video below Birrer explains that, “pre-operatively and during therapy physicians will usually check CA-125 as a measure of the effectiveness of the therapy. At the completion of therapy one would anticipate that the CA-125 would be normal. After that, it is somewhat controversial as to whether follow-up with CA-125 to test for recurring disease is clinically relevant,” says Birrer. Since the discovery of CA-125 in 1981, there has been intense research focus on novel biomarkers for cancer, and significant scientific advances in genomics, proteomic, and epigenomics etc., which have been extensively used in scientific discovery, but as yet no new major cancer biomarkers have been introduced to practicing oncologists.

Limited treatment options

As most ovarian cancer patients are diagnosed late when the disease has already spread, treatment options are limited. The first line treatment is surgery called debulking, (also known as cytoreduction or cytoreductive surgery), which is the reduction of as much of the volume (bulk) of a tumor as possible.

Be prepared for extensive surgery

Whether a patient is a candidate for surgery depends on a number of factors including the type, size, location, grade and stage of the tumor, pre-existing medical conditions, and in the case of a recurrence, when the last cancer treatment was performed, as well as general health factors such as age, physical fitness and other medical comorbidities. People diagnosed with ovarian cancer, “need to be prepared to have extensive surgery because the real extent of the tumor dissemination cannot be detected by conventional imagining pre-operatively,” says Professor Christina Fotopoulou, consultant gynaecological oncologist at Queen Charlotte's & Chelsea Hospital, London: see video below.

Platinum resistance

Surgery is usually followed by chemotherapy. There are more than 100 chemotherapy agents used to treat cancer either alone or in combination. Chemotherapy drugs target cells at different phases of the process of forming new cells, called the cell cycle. Understanding how these drugs work helps oncologists predict, which drugs are likely to work well together. Clinicians can also plan how often doses of each drug should be given based on the timing of the cell phases. Chemotherapy drugs can be grouped by their chemical composition, their relationship with other drugs, their utility in treating specific forms of cancer, and their side effects.

“You can reduce chemotherapy resistance by using a combination of drugs that target different processes in the cancer so that the probability that the cancer will simultaneously become resistant to both drugs is much lower than if you use one drug at a time, ” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia: see video:

Improving the chemotherapy agent cisplatin

The standard chemotherapy treatment for ovarian cancer is a combination of a platinum compound, such as cisplatin or carboplatin, and a taxane, which represents a class of drug originally identified from plants. Since cisplatin’s discovery in 1965 and its FDA approval in 1978, it has been used continuously in treatments for several types of cancer, and is best known as a cure for testicular cancer. Scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing their toxicity, strengthening them against resistance by expanding the class to include several new analogues of cisplatin, and putting these through clinical studies to broaden the different types of cancers against which they can be safely used.

Slow progress transitioning research into clinical practice

Despite these endeavors, platinum resistance remains a significant clinical challenge. Between 55 and 75% of women with ovarian cancer develop resistance to platinum based chemotherapy treatments. Significant research efforts have been dedicated to understanding this, but there has been relatively slow progress transitioning the research into effective clinical applications. According to Birrer, “the mechanism of platinum resistance from a molecular standpoint has not been well defined. It is likely to be heterogeneous, which means that each patient’s tumor may be slightly different. The hope is for targeted therapies and personalised medicine to have a chance of overcoming this, in that we could characterize the mechanism of the platinum resistance and apply and target therapy.”

2 theories of platinum resistance

In the video below, Birrer posits 2 theories to explain platinum resistance. “One suggests that under the influence of platinum the tumor changes and becomes resistant. Another suggests that there are 2 groups of cells to begin with. The vast majority of the tumor is sensitive, but there are small clusters of resistant cells. Once you kill the sensitive cells you have only the resistant cells left. Although these 2 theories have been around for about 25 years, there are no definitive data to suggest which theory is right. I have a personal scientific bias to think that the resistant cells are present at the time that we start the therapy. Being able to identify and characterize these cells upfront would be a radical breakthrough because then we would be able to target them at a time when they are only a small portion of the tumor,” says Birrer.

Takeaways

Saatchi is right; for decades ovarian cancer treatment has been wanting, but studies we describe in part-2 of this Commentary suggest that the tide might be turning for people living with ovarian cancer. So don't miss part-2 next week!

Directory:

Tags:

The clandestine status of cannabis and its attendant risks are beginning to erode

The idea of cannabis as an evil drug is a relatively recent phenomenon

Plants have been the historical source of medicine for most of human history, and cannabis is no exception

There is a large and growing pharmacological and clinical interest in cannabis as medicine

Two distinct legal markets for cannabis are emerging: the tightly regulated pharmaceutical market and the less regulated market of herbal preparations

The FDA has approved cannabis-related drugs, which are used for a number of indications

There may be a recognizable pathway leading to more cannabis compounds becoming medicine

To become accepted as a medicine that doctors prescribe, pharmacists supply and healthcare providers support, cannabis compounds need to demonstrate their biochemical uniformity, stability, safety and efficacy

Medical cannabis and modern healthcare

Today, cannabis medicine for most people involves the black market with its attendant risks and lack of quality control. But this is changing to a more desirable alternative. As legal opinion changes, and clinical studies increase; the clandestine nature of cannabis and its attendant risks are beginning to erode, and two distinct legal markets for medical cannabis are emerging. One is the tightly regulated pharmaceutical market where medical cannabis provides safe and effective pharmaceutical solutions, which doctors prescribe, pharmacists’ supply, and healthcare providers support, and the other is the less regulated market of herbal preparations. A report by ArcView Market Research reported that 2016 annual sales of legal cannabis in the US grew by 25%, to US$6.7bn, and projects sales will reach US$21.8bn by 2020. This Commentary focuses on the pharmaceutical market, which relies on randomized clinical studies to demonstrate biochemical consistency, safety and efficacy.

The cannabis plant and its main properties

Cannabis is a genus of an annual herbaceous flowering plant, which includes 2 familiar sub-species or chemovars: ‘C sativa’, and ‘C indica’. Modern molecular techniques applied to the taxonomic classification of cannabis have resulted in many more classifications, which, in time, will become increasingly relevant as the plant’s medicinal qualities are increasingly identified. Cannabis is an indigenous plant of central Asia and India, but can be grown in almost any climate in any part of the world, and is increasingly being cultivated by means of indoor hydroponic technology. The cannabis plant contains more than 100 cannabinoids, which are chemical compounds secreted by cannabis flowers. About 60 of these have been identified as pharmacologically active, with the primary active cannabinoids being delta-9-tetrohydro-cannabinol, commonly known as THC, and cannabidiol, which is commonly known as CBD. THCprovides the principal mind-altering ingredient, while CBD does not affect the mind or behavior.

Cannabis as medicine

Medical cannabis refers to using extracts from the cannabis plant - cannabinoids - to treat a range of conditions or their symptoms. Cannabinoids can be administered orally, sublingually, or topically; they can be smoked, inhaled, mixed with food, or made into tea. When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain and body. Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds with receptors in the brain called CB-1, while CBD has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable. THC is the most active cannabinoid; it has dominated research into medical cannabis and resulted in FDA-approved drugs. Although CBD is one of the least active cannabinoids, it has come to dominate more recent research into medical cannabis as it is considered to have a relatively wide scope of potential medical applications with fewer side effects than THC.

Pot-ted history

Plants have been the historical source of medicine for most of human history, and continue to account for the base material of about 25% of modern pharmaceuticals. Approved medicines of botanical origin are relatively common, but require evidence-based randomized clinical studies to demonstrate their biochemical uniformity, stability, safety and efficacy. Medical cannabis is no exception, and the FDA has approved drugs derived from cannabinoids and synthetic cannabinoids. However, regulators have not approved the entire cannabis plant as medicine because there are insufficient clinical studies to demonstrate its benefits against its potential risks to patients it is meant to treat.

For centuries the cannabis plant has been used throughout the world for medicinal purposes. Only in recent history has it acquired the status of a dangerous drug and banned. Its first recorded use is 4000 BC when an extract from the cannabis plant was used in China as an anesthetic during surgery. The Chinese went on to use cannabis compounds extensively for a range of conditions including malaria, constipation, rheumatic pains, "absentmindedness" and "female disorders."

From China, cannabis travelled throughout Asia into the Middle East, Africa, Europe, and eventually to the US. Galen, a prominent Greek doctor and scientist in the Roman Empire, noted cannabis as a remedy. In India it was used to lower fevers, quicken the mind, induce sleep, cure dysentery, stimulate appetite, improve digestion, relieve headaches, and cure venereal disease. The Vikings and medieval Germans used cannabis for toothache, and for relieving pain during childbirth. In Africa it was used for a variety of fevers including malaria. Despite its extensive medicinal use in early history, there were warnings against the over-use of cannabis as it was said to result in “seeing demons”.

Opinion changing

The idea of cannabis as an evil drug is a relatively recent phenomenon. Despite its contemporary clandestine status, there is a large and growing pharmacological and clinical interest in cannabis as medicine, and a recognizable pathway leading to its return to mainstream medicine. As early as 1985 the FDA approved cannabinoids as medicine. As of June 2016, 25 American states and Washington DC, have legalized cannabis for medical use. Germany is now expected to follow suit. In the UK, more than half of its national parliamentarians, including the former deputy Prime Minister, want to see the legalisation of medical cannabis. In March 2017, Oxford University announced that it is to launch a £10m global centre of excellence in cannabinoid research. The program, which is a partnership between the University and Kingsley Capital Partners, a private equity business based in London, will examine the role of cannabis medicines in treating pain, cancer and inflammatory diseases.

FDA approved

The FDA has approved two cannabis-related drugs: dronabinol and nabilone. The former contains the psychoactive compound THC extracted from the resin of C-sativa. The latter contains a synthetic cannabinoid, which mimics THC; the primary psychoactive compound found naturally occurring in cannabis. Both treat chemotherapy-induced nausea and vomiting (CINV), and extreme weight loss caused by HIV/AIDS, among a number of other indications.

Nabiximols, a CBD extract of cannabis, has been approved in 27 countries as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Although it has not yet undergone clinical studies, scientists have recently developed Epidiolex, a CBD-based liquid drug to treat certain forms of childhood epilepsy.

Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV), is one of the most common and feared adverse events that can be experienced by cancer patients. Its occurrence depends on the dose and the type of chemotherapy agent used, but it tends to be more prevalent in anxious woman under 50 who do not drink alcohol, and who have a history of sickness during pregnancy. Despite advances in the prevention and treatment of emesis, of the 70% to 80% of cancer patients who experience CINV, many delay or refuse future chemotherapy treatments, and contemplate stopping all treatments because of fear of further nausea and vomiting.

There are several drug classes for the prevention and management of CINV. In 1985 the FDA approved a cannabinoid, dronabinol, for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment. The number of people taking cannabinoids for therapeutic purposes is increasing, but very few medicines based on cannabis have yet been developed on rigorous scientific principles. Ahmed Ahmed, professor of gynaecological oncology at Oxford says, “This field holds great promise for developing novel therapeutic opportunities for cancer patients.”

The endogenous cannabinoid system is a significant pathway involved in the emetic response. Cannabinoids can reduce or prevent chemotherapy-induced emesis by acting at central CB-1 receptors by preventing the pro-emetic effects of endogenous compounds, such as dopamine and serotonin. In addition, by acting as an agonist to CB-1, cannabinoids used as a treatment result in an antiemetic effect. Notwithstanding, few studies have evaluated medical cannabis alone or in combination to treat CINV. The published studies that have been conducted have mixed results. THC has to be dosed relatively highly, so that resultant adverse effects may occur comparatively frequently. Some investigations suggest that THC in low doses improves the efficacy of other antiemetic drugs if given together.

Some additional indications

In addition to its ability to reduce nausea, THC is effective as an appetite stimulant in both healthy and sick individuals, and is used to boost appetite in patients with cancer, HIV-associated wasting syndrome, and patients with anorexia.

Another common use of medical cannabis is as an analgesic. Studies suggest that THC activates pathways in the central nervous system, which work to block pain signals from being sent to the brain. THC has been shown to have some effect against neuropathic, cancer and menstrual pain, headache, and chronic bowel inflammation.

The high, which users get from cannabis THC is also associated with temporary loss of memory. For most people this would be concerning, but for people with post-traumatic stress disorder (PTSD), memory loss can be positive. PTSD is a chronic, disabling mental health condition triggered by a significant event, and results in traumatic flashbacks, nightmares, and emotional instability. A 2013 study published in the journal Molecular Psychiatry reported a correlation between the quantity of cannabinoid CB-1 receptors in the human brain and PTSD, and concluded that oral doses of THC could help relieve PTSD-related symptoms.

Review of clinical studies

In 2015 a systematic review of the pros and cons of cannabinoids was published in the Journal of the American Medical Association. The paper analyzed 79 clinical studies of cannabinoids, involving 6,462 participants, for a number of indications including: CINV, chronic pain, appetite stimulation in HIV/AIDS, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome.

Most studies in the review showed improvement in symptoms that were correlated with cannabinoids, compared with a placebo. However, symptoms positively correlated with cannabinoids did not reach statistical significance in all studies. The review reported that there was an increased risk of short-term adverse effects associated with cannabinoids, some of which were severe. Common among these were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

The review concluded that, “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were correlated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were also correlated with an increased risk of short-term adverse effects.”

Clinical studies design challenges

Although cannabis compounds are currently used to treat disease or alleviate symptoms for a number of conditions, their efficacy for some specific indications is not altogether clear. This reflects the relative dearth of clinical studies that have been carried out on cannabinoids. Further, there are several design challenges associated with clinical studies that involve THC. One is whether cannabis components beyond THC contribute to its medicinal effects. Another is connected with the ability of studies to provide adequate blinding for psychoactive compounds such as THC. Clinical studies generally are known to show a degree of subjective improvement associated with the additional attention participants in a study are given, and this is compounded when a clinical study outcome measures subjective responses, such as pain and mood, as in the case of THC.

Gold standard

To be accepted by doctors, supplied by pharmacists and supported by healthcare providers, a medical cannabis product must be standardized and consistent, and display a quality equal to any recognized pharmacological compound. It must have a secure supply chain, possess an appropriate low-risk delivery system, and have minimal adverse effects. Although there are entities working to bring this about, the fact remains that the overwhelming majority of cannabis available today is unregulated, and this provides significant challenges, which include the biochemical variability of one chemovar to another, the possibility of the presence of bacteria and pesticides, and the variation in potency.

Nabiximols

A significant success of medical cannabis is nabiximols, an oromucosal spray produced from whole cannabis extracts, which is used to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Currently nabiximols is available in 27 countries, is biochemically uniform and provides an easy-to-use, reliable delivery system with immediate onset, allowing a therapeutic window for control of symptoms without intoxication. This suggests a gold standard benchmark, which other cannabis-based medicines will be required to follow.

Takeaways

There seems to be a clear pathway for medical cannabis to increase in importance in modern pharmacology. Modern technology, which facilitates advanced cultivation and extraction processes appear to be well positioned to facilitate the creation and development of cannabis products to target specific medical needs for maximum relief of a number of chronic conditions.

Genetic test results for breast cancer are fraught with uncertainty because testing reveals the likelihood of developing cancer rather than a certain fate

Research suggests that BRCA test results are not being clearly communicated to women

Best practice demands that expert counselors discuss genetic testing and help interpret results

Breast cancer and harmful BRCA gene mutations

Few things frighten women more than discovering a lump in one of her breasts The standard treatment: surgery, followed by radio- and chemotherapy, can be disfiguring, painful, sometimes unsuccessful, and the impact of the disease is felt by far more individuals than just those who have the diagnosis.The good news is that over the past 30 years breast cancer survival rates in most developed countries have been improving, largely due to screening, earlier diagnosis and improved treatments. The bad new is that in most developed countries it is twice as likely for a woman to be diagnosed with breast cancer than 60 years ago.

Harmful BRCA genes mutations

5 to 10% of breast cancers are thought to be due to gene mutations, and harmful BRCA mutations account for 20 to 25% of these. Women who inherit the BRCA1 mutations have a 60 to 90% risk of developing breast cancer in their lifetime, and those who inherit BRCA2 mutations increase their risk of breast cancer by 45 to 85%, compared to 12% of women in the general population. Most women do not know if they carry the harmful BRCA mutation, but if they discover they do, many elect to have a bilateral mastectomy. This is a significant procedure with potential risks and side effects, but can reduce your mortality risk by about 50%.

The gold standard screening for breast cancer is an x-ray picture of the breast (mammography), but increasingly women are turning to genetic testing as their awareness of the harmful BRCA mutations increase, and genetic testing becomes more accessible and affordable. However, results from these tests are not straightforward, and often not communicated well. This can increase the anxiety in women with suspected breast cancer, and make them elect to have unnecessary interventions and procedures.

This Commentary describes how advanced genetic testing together with expert counselling help women improve their management of breast cancer.

Breast Cancer

Cancer is a group of diseases that cause cells in your body to change and grow out of control: they mutate. Most types of cancer cells eventually form a lump or mass called a tumor, and are named after the part of the body where the tumor originates, e.g. “breast cancer”, although this convention is changing with the development of targeted personalized medicine. The exact cause of breast cancer is unknown, but the overwhelming majority result from some combination of environment, lifestyle, and genes. Breast cancer affects about 1 in 8 women at some point during their life, usually after the menopause, and is the most common cancer in women. The majority of breast cancers begin in the parts of the breast tissue that are made up of glands for milk production, called lobules, and ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective, and lymphatic tissue. Most invasive breast cancers (those that have spread from where they started) are found in women 55 and older.Women with a family history of the disease have an increased risk of getting breast cancer. Each year about 1.7m women are diagnosed with breast cancer worldwide, and over 0.5m die from the condition. However in developed economies more and more women survive the disease. In the US, for instance, the average 5-year survival rate for people with breast cancer is 89%. The 10-year rate is 83%, and the 15-year rate is 78%. Other developed countries have similar success rates. What makes breast cancer fatal is if it spreads to the bones, lungs, liver and other organs. Early detection in order to improve breast cancer outcomes remains the cornerstone of the condition’s management. Although breast cancer is thought to be a disease of the developed world, it is increasing rapidly in emerging countries where the majority of cases present later and die earlier than women in developed countries: almost 50% of breast cancer cases and 58% of deaths occur in emerging economies. This is because women generally have relatively poor knowledge of the risk factors, symptoms and methods for early detection. Also, they experience cancer fatalism, believe in alternative medicine, and lack of autonomy in decision making, which often results in delays in seeking or avoidance of evidence-based medicine.

Mammography

Mammography, which has long been the mainstay of breast cancer detection, is a specific type of breast imaging that uses low-dose x-rays to detect small changes in the breast before there are any other signs or symptoms of the disease when it is most treatable. Mammography is noninvasive, relatively inexpensive, and has reasonable sensitivity (72–88%), which increases with age. It can also be used to detect and diagnose breast disease in women experiencing symptoms such as a lump, pain, or nipple discharge. If breast cancer is found at an early stage, there is an increased chance for breast-conserving surgery and a better prognosis for long-term survival. Most developed countries operate breast-screening programs, which regularly provides mammography for women between certain ages.

Advances in mammography

In recent years, mammography has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dosage, cost and patient anxiety. In response to these challenges, new forms of mammography screening have been developed, including; low dose mammography, digital mammography, computer-aided detection, tomosynthesis, which is also called 3-D mammography, automated whole breast ultrasound, molecular imaging and MRI. Notwithstanding, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. More recently, women have turned to genetic testing to gain a better understanding of their risk of inherited breast cancer.

Genes

Every cell in your body contains genes. These contain the genetic code for your body, which not only determines the color of your eyes and hair etc., but also provides information that affects how the cells in your body behave: for example, how they grow, divide and die. Information in your genes is inherited from both parents, and you pass on this information to your children. A change in your genetic code that affects the function of a gene is called a mutation. Many inherited gene mutations do not have any effect on your health, but some do; the BRCA1 and BRCA2 mutations account for 20 to 25% of all inheritable female breast cancers and 15% of ovarian cancers.

BRCA genes

In normal cells, BRCA genes are tumor suppressor genes that assist in preventing cancer developing by making proteins that help to keep cells from growing abnormally. Mutated versions of BRCA genes cannot stop abnormal growth, and this can lead to cancer. Mutated BRCA genes have a higher prevalence in certain ethnic groups, such as those of Ashkenazi Jewish descent.

In the video below Professor Robert Leonard,a medical oncologist and an authority on breast cancer, describes how BRCA genes are influential in breast and ovarian cancer risk. BRCA1 runs in families and may also increase a woman’s risk of developing fallopian tube and peritoneal cancers. BRCA2 also runs in families, and is more breast cancer-specific, but a less commonly inherited abnormality. Both or either of these genes may not be detectably abnormal even in a family with a strong inherited pattern of breast cancer, but there is a significant possibility that you will find them in people with a family history of breast and ovarian cancer. Breast and ovarian cancers associated with BRCA mutations tend to develop at younger ages than their non-hereditary counterparts.

Enhanced risk when family members have cancer

In December 2013, the US Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a familial history that is associated with an increased risk of a harmful mutation in one of the BRCA genes. Compared to women without a family history of cancer, risk of breast cancer is about 2 times higher for women with a close female relative who has been diagnosed with cancer; nearly 3 times higher for women with two relatives, and nearly 4 times higher for women with three or more relatives. Risk is further increased when the affected relative was diagnosed at a young age. Notwithstanding, the Preventive Services Task Force recommends against BRCA testing for women with no family history of cancer.

The Angelina Jolie effect

The Hollywood actress and filmmaker Angelina Jolie lost her grandmother and aunt to breast cancer and her mother to ovarian cancer. After discovering that she carried a maternally inherited pathogenic BRCA1 mutation, and being told that she had an 87% chance of developing breast cancer, and a 50% chance of ovarian cancer, Jolie elected to have her breasts, ovaries and fallopian tubes removed. After surgery her risk of developing breast cancer in later life fell to 5%.

In May 2013, Jolie described her decision in a New York Times (NYT) article, “I am writing about it now because I hope that other women can benefit from my experience . . . . . Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”

Over testing of by low-risk women

Findings published in December 2016 in the British Medical Journalsuggest that tests for the BRCA genes shot up by 64% following Jolie’s article. Researchers analysed data on US health insurance claims from more than 9m women between 18 and 64, and suggested that in just 2 weeks following Jolie’s NYT disclosure, 4,500 additional BRCA tests were carried out, which cost the US healthcare system some US$13.5m. Interestingly, increased testing rates were not accompanied by a corresponding increase in mastectomy rates, which suggests that additional testing did not identify new BRCA mutations. Thus, the Angela Jolie effect might have encouraged over-testing among low-risk women.

Mindful of her influence on women’s decisions, in 2015 Jolie wrote another NYT article in which she attempted to correct her earlier support for radical risk reduction surgery for women carriers of BRCA mutations. She said that because surgery worked for her, it is not necessarily the optimal therapeutic pathway for all women, and stressed that non-surgical treatments could be more appropriate.

Genetic testing to detect BRCA mutations has been available since 1996, but for many years it was under-used because of its scarcity, high cost, and the length of time it took to produce a result. The rapid development and plummeting costs of genetic testing, and a 2013 US Supreme Court ruling, which invalidated the patents held by Myriad Genetics Inc., which restricted BRCA testing, have resulted in the growth and accessibility of genetic testing.

BRCA testing is not straightforward

There are hundreds of mutations in the BRCA1 and BRCA2 genes that can cause cancer. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member), and tests that check for all possible mutations in both genes. Commercial laboratories usually charge between US$450 and US$5,000 to carry out BRCA testing, depending on whether you are being tested for only a specific area(s) of a gene known to be abnormal or if hundreds of areas are being examined within multiple genes. Tests that use traditional technology take several months to report findings. This means that even if a woman is tested at the time of diagnosis, she might not know the results before she has to decide on treatment.

Importance of regulated testing laboratories

Testing for the BRCA genes usually involves a blood sample taken in a doctor’s clinic and sent to a commercial laboratory. In 1988, the US Congress passed the Clinical Laboratory Improvement Amendments (CLIA) to ensure quality standards, and the accuracy and reliability of results across all testing laboratories. Since then, all legitimate genetic testing in the US is undertaken in CLIA-approved facilities. During testing for BRCA mutations, the genes are separated from the rest of the DNA, and then scanned for abnormalities. Unlike other clinical screening such as HIV tests and colonoscopies, which provide a simple positive or negative result; genetic testing is fraught with uncertainty because it reveals the likelihood of developing cancer rather than a certain fate.

BRCA1 and BRCA2 genetic test results

A positive BRCA test result indicates that you have inherited a known harmful mutation in the BRCA1 or BRCA2 gene. This means that you have an increased risk of developing breast and ovarian cancers, but it does not mean that you will actually develop cancer. Some women who inherit a harmful BRCA mutation will never develop cancer. A positive test result may create anxiety and compel clinicians to perform further tests and women to undergo premature and unnecessary clinical interventions, other women in a similar situation will opt for regular screening.

The potential benefits of a true negative result include a sense of relief regarding your future risk of cancer, learning that your children are not at risk of inheriting the family's cancer susceptibility, and that a range of interventions may not be required. However, a negative result sometimes can be difficult to interpret because its meaning partly depends on your family’s history of cancer, and whether a BRCA mutation has been identified in a blood relative. Further, scientists continue to discover new BRCA1 and BRCA2 mutations, and have not yet identified all potentially harmful ones. Therefore, it is possible that although you have a “negative” test result you might have a harmful BRCA1 or BRCA2 mutation, which has not been identified.

Counselling

Because of these uncertainties and the agonising choices women with suspected breast cancer face, health providers in most developed countries recommend counselling as part of breast cancer treatment pathways. In the video below Dr John Green, a medical oncologist knowledgeable about the influence of inherited BRCA gene mutations on treatment options underlines the importance of expert genetic counselling to help women navigate their therapeutic pathways. Counselling is performed by a health professional experienced in cancer genetics, and usually includes the psychological risks and benefits of genetic tests, a hereditary cancer risk assessment based on a person’s personal and family medical history; a description of the tests, their technical accuracy and appropriateness, medical implications of a positive or a negative test result, the possibility of uncertain or ambiguous test results, cancer risk-reducing treatment options, and the risk of passing on a mutation to children. Because people are more aware of the genetic mutations linked to breast cancer, the demand for genetic testing and counselling have increased, and in some instances it is challenging for genetic counsellors to keep pace with demand.

The context in which genetic tests are carried out

A 2017 study published in the Journal of Clinical Oncology suggests that genetic test results for breast cancer are not being clearly communicated to women, and this could cause them to opt for treatments that are more aggressive than they actually need. To reduce this possibility the Royal Marsden NHS Trust Hospital in London has introduced theMainstreaming Cancer Genetics programme. Since 2014 the Marsden has employed genetic counseling and used laboratories with enhanced genetic testing capabilities. This reduces processing time and costs, helps to meet the increased demand for rapid, accurate and affordable BRCA testing, and helps women make critical decisions about their treatment options.

“There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex,” says Nazneen Rahman, Professor and Head of Cancer Genetics at the UK’s Institute for Cancer Research in London. “We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital,” says Rahman.

The Marsden is now offering tests to three times more patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.”

Takeaways

The history of cancer is punctuated with overzealous interventions, many of which have had to be modified once it has been demonstrated that they could cause more harm than good.

As advanced genetic testing becomes affordable and more accessible it is important that their results are interpreted with the help of genetic counsellors in a broader familial context in order to help women make painfully difficult decisions about their treatment.

Migration to next generation genetic testing technologies has many benefits, but it also introduces challenges, which arise from, the choice of platform and software, and the need for enhanced bio-informatics analysts, which are in scarce supply. An efficient, cost-effective accurate mutation detection strategy and a standardized, systematic approach to the reporting of BRCA test results are central for diagnostic laboratories wishing to provide a service during a time of increasing demand and downward pressure on costs.

Directory:

Tags:

3m men in the US and 330,000 men in the UK are living with prostate cancer

The standard test used to diagnose prostate cancer is inaccurate

This inaccuracy causes anxiety in men and leads to unnecessary treatments

Standard therapies for prostate cancer can result in incontinence and impotence

Two new studies describe procedures that promise significant improvements in diagnosis and treatment

New developments in the management of prostate cancer

A vicious circle

There is general agreement on two issues concerning the management of prostate cancer: one, over-diagnosis and overtreatment rates are high; and two, there is a need to refine the standard prostate-specific antigen (PSA) diagnostic test.

The test does not provide information to allow doctors to determine which early-stage prostate tumors pose a risk of being aggressive and need treatment, and which should be left alone. Therefore, efforts to reduce the prevalence of prostate cancer by early detection using the PSA test can lead to over-diagnosis, which in turn can result in overtreatment, which in the case of prostate cancer, can result in incontinence and impotence.

Current official advice to UK GPs says: “The PSA test is available free to any well man aged 50 and over who requests it.” But, “GPs should not proactively raise the issue of PSA testing with asymptomatic men”. And, “GPs should use their clinical judgment to manage symptomatic men and those aged under 50 who are considered to have higher risk for prostate cancer”. In 2014 the National Institute for Health and Care Excellence (NICE) updated its guidelines and suggested that prostate cancer patients should avoid immediate treatment and keep their disease under “surveillance”.

A killer disease on the increase

Prostate cancer is increasing in significance worldwide. In many industrialized countries such as the US and the UK, it is one of the most common cancers and among the leading causes of cancer deaths. In developing countries it may be less common, but its incidence and mortality rates have been on the rise. In the US there are some 3m men living with the disease. It is expected that in 2017, 161,000 new cases of prostate cancer will be diagnosed in the US, and 27,000 men will die from it. In the UK, there are some 330,000 men living with prostate cancer; each year around 47,000 men are diagnosed with the disease, and each year some 11,000 die from it, which equates to one every hour. Worldwide, there are an estimated 1.6m new cases of prostate cancer, and 366,000 prostate cancer deaths annually, making it the most commonly diagnosed cancer in men and the seventh leading cause of male cancer death.

The prostate and prostate cancer

The prostate is a small gland in men, which is located below the bladder and above the rectum. The urethra, which is the tube that carries urine and semen out of the body through the penis, goes through the centre of the prostate. In younger men the prostate is about the size of a walnut, but in older men it can be much larger. Symptoms of prostate cancer include persistent burning, difficult, frequent, uncontrolled or bloody urination in the absence of any infection. The average age of onset is 65 to 69. It is particularly prevalent in African-Caribbean men: affecting I in 4, and killing I in 12, which is double the rate for that of Caucasian men. The main risk factor is age: 80% of all men diagnosed with prostate cancer are over 65. Between 5% and 9% of cases occur in men with a family history of prostate, breast or ovarian cancer. Environmental factors are unclear, but rates of prostate cancer are lower in less urbanised societies, and rates rise when people move to a more westernised diet and lifestyle.

The prostate-specific antigen (PSA) test

In the 1980s a simple and cheap blood test was introduced to detect prostate cancer in its earliest, most curable, stage. In the video below Professor Karol Sikora, a cancer expert, describes the PSA test. Although used to detect prostate cancer, it is not a test for prostate cancer, and as a consequence, it has unresolved challenges. The most significant arises because the test is not accurate enough to either rule out or confirm the presence of cancer. Indeed, it is possible for PSA levels to be elevated when cancer is not present, and not to be elevated when it is present. More than 65% of men with elevated PSA levels do not have cancer. Excessive reliance on the test may lead to unnecessary interventions, while insufficient reliance may cause cancers to be missed.

Biopsies

A biopsy will often be recommended if a PSA test is high. It may also be recommended if a digital rectal examination (DRE) reveals a lump or some other abnormality in the prostate. The most commonly used biopsy for diagnosing prostate cancer is the trans-rectal ultrasound-guided prostate biopsy (TRUS-biopsy). This is a surgical procedure, in which tissue is removed from the prostate for microscopic examination. Each year, over 100,000 prostate biopsies are carried out in the UK and 1m in Europe.

75 to 80% of men who have TRUS-biopsies have no cancerous cells, and therefore did not need the biopsy. 20 to 25% do have cancerous cells, but a large percentage of these do not need any treatment because the cancers are slow growing. A 2014 paper by the Harvard School of Public Health estimates that only 3% of men suspected of prostate cancer have an aggressive tumor requiring immediate intervention.

Further, doctors cannot tell from a biopsy whether cancerous cells are aggressive and need treatment, or whether they are developing slowly and do not require treatment. This creates confusion and anxiety among men, which prompts a percentage to opt for treatment even though the overwhelming majority do not need it. 25% of older men who elect to have treatment will become incontinent or impotent as a result, despite the fact that they did not need the treatment.

Active surveillance

In a significant proportion of men, prostate cancer cells grow slowly and never pose a serious risk to health and longevity. Evidence suggests that early treatment with either surgery or radiation does not reduce mortality rates, but leaves a significant percentage of men with urinary or erectile problems and other adverse effects. As a result, more men are willing to manage their condition by active surveillance, in which doctors monitor low-risk cancers closely and consider treatment only when the condition appears to make threatening moves toward growing and spreading. These men choose to live with prostate cancer until it advances, sometimes avoiding potentially life-altering side effects for several years. Active surveillance is a powerful solution to the problem of over-diagnosis and overtreatment.

New studies promise significantly improved management

Prostate cancer lags behind other cancers in diagnosis, treatment and research funding. But this is beginning to change. Over the past year, findings of two clinical studies promise significant improvements in the management of the condition.

The first, published in 2017 in the Lancet, describes a process, which uses MRI-guided biopsies to improve the accuracy of prostate cancer diagnosis, and spares those who do not have aggressive cancers from undergoing an unnecessary biopsy, so reducing the confusion and anxiety which prostate patients often experience.

The second, published in 2016 in the Lancet Oncology, describes findings of a laser-activated drug derived from bacteria found at the bottom of the sea that attacks and kills prostate cancer cells without either removing or destroying the prostate gland. This is significant because it avoids the potential adverse effects of surgery and radiotherapy, which can render patients incontinent and/or impotent.

The multi-parametric MRI

The 2017 Lancet study used an advanced type of MRI scan, known as a multi-parametric MRI (MP-MRI), which in addition to recording the shape and size of the prostate, also assesses the blood flow through the gland. Led by Dr Hashim Ahmed of University College London, the study was comprised of more than 500 British men with suspected prostate cancer. Results suggest that using the MP-MRI to triage men would safely reduce the number needing a primary biopsy by about 27%, and substantially improve the detection of clinically significant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancers might be detected compared with the standard pathway of TRUS-biopsy for all.

A paradigm shift in prostate cancer treatment

The second study compared the safety and effectiveness of a new therapy called vascular-targeted photodynamic therapy (VTP, also known as TOOKAD), with active surveillance in men with low-risk prostate cancer. It funded by STEBA Biotech, which holds the commercial licence for the therapy. Photodynamic therapy (PDT) is not new, and has been used to treat skin and other cancers where light can easily penetrate. VTP therapy, however, is viewed as a paradigm shift in prostate cancer care. It involves injecting a light-sensitive drug (padeliporfin or WST11) into the bloodstream, and then activating it with a laser to destroy cancerous tissue. The benefit of this approach is damage to healthy prostate tissue is minimised, reducing the risk of side effects.

Findings

The study was comprised of 413 men at low risk of prostate cancer, and carried out across 47 treatment sites in 10 European countries, most of which were performing VTP therapy for the first time. Only men classified with low-risk cancer were included in this study. Participants were randomly assigned either to VTP therapy or active surveillance. At the end of two years, of the 196 men who received the VTP treatment, about half showed no signs of the disease, compared with 13.5% of those given standard care. Only 6% of the VTP group later needed radical treatment, compared with 30% of active surveillance patients. VTP treatment also doubled the average time of cancer progression from 14 to 28 months. Findings suggest that 49% of patients treated with VTP therapy went into complete remission compared with 13.5% in the control group.

A third of the VTP group experienced side effects compared to only 10 of the active surveillance group. Notwithstanding, the study concluded that, “VTP therapy is a safe, effective treatment for low-risk, localised prostate cancer, which might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy”. Patient monitoring will continue in order to ascertain whether the cancer stays away. Further studies should help to understand better which cancers VTP treatment is most appropriate for so that men can make more informed treatment decisions.

Study enhanced by MRI scanning

The study was conducted with people at low risk of prostate cancer. Those at very low risk are better off with no treatment and no adverse-effects. Professor Mark Emberton of University College London, the lead author of the study, believes the therapy will be most useful in patients in the “grey zone”, between low and high risk. “The fact that the treatment was performed so successfully by non-specialist centres in various health systems is really remarkable”, says Emberton because the lack of complication suggests that the treatment protocol is safe, and relatively easy to scale.

At the beginning of the study MRI scans were not universally available, and Emberton believes MRI scanning as suggested by the Ahmed 2017 study will have a significant positive effect on prostate cancer treatment in the future. When carrying out biopsies without guidance from MRI scans researchers had to guess where in the prostate the cancer was; so biopsies were sub-optimal. “If they were to do the study now, with the help of MRI scans, they could hit the cancerous parts of the prostate rather than going in blind and the results would be much better,” says Emberton.

Takeaways

These two recent studies are potential “game changers”. They promise to significantly enhance the management of prostate cancer and substantially reduce the uncertainty and anxiety, as well as the risks of the life altering side effects of treatment, experienced by millions of men living with the disease.

Nearly half of all cancer sufferers are diagnosed late when the tumors have already spread

Victims and doctors often miss early warning signs of cancer

Traditional tissue biopsies used to diagnose cancer are invasive, slow, costly, and often yield insufficient tissue

New blood tests are being devised that simultaneously detect cancer early and inform where the cancer is in the body

Such tests - liquid biopsies - are positioned to end the late diagnosis of cancer

But before liquid biopsies become common practice they need to overcome a number of significant challenges

World’s first blood tests that detect and locate cancer

Just as there is a global race among immunotherapists to enhance cancer treatment, so there is a parallel race among bioengineers to speed up and improve the detection of cancer. Such races are important because nearly half of all cancer sufferers are diagnosed late, when their tumors have already metastasized: 30% to 40% of cancer deaths could be prevented by early detection and treatment.

Here we describe advances in blood tests - “liquid biopsies” - which can simultaneously detect cancer early, and identify its tissue of origin. We also, describe the growing commercialization of the technology, and some significant hurdles it still has to be overcome.

A costly killer disease

Each year cancer kills more than 8m people worldwide, 0.6m in the US and nearly 0.17m in the UK. Survival rates for pancreatic, liver, lung, ovarian, stomach, uterine and oesophageal cancers are particularly low. A large proportion of people do not know they have cancer, and many primary care doctors fail to detect its early warning signs. According to The Journal of Clinical Oncology, a staggering 44% of some types of cancers are misdiagnosed. A significant proportion of people discover that they have cancer only after presenting a different condition at A&E. Each year, the total cost of cancer to the UK’s exchequer is nearly £20bn. In the US, national spending on cancer is expected to reach US$156bn by 2020. And as populations age so some cancer prevalence rates increase, despite substantial endeavours to reduce the burden of the disease.

The UK: a stereotypical case

The UK is indicative of what is happening elsewhere in the developed world with regard to cancer diagnosis and treatment. Epidemiological trends suggest that although progress is being made to fight the disease, much work is still required. Death rates for a number of individual cancer types have declined, but rates for a few cancers have increased.

Recently, the UK’s Department of Health invested £450m to improve diagnosis, including giving primary care doctors better access to tests such as CT and MRI scans. But each year there are still some 0.17m cancer deaths in the UK, and 1 in 4 British cancer patients are unlikely to live longer than 6 months after diagnosis because they and their doctors have missed early signs of the disease. For example, in the UK only 23% of lung cancer cases are diagnosed early, as are 32% of cases of non-Hodgkin lymphoma, and 44% of ovarian cancer.

Not only does late detection increase morbidity and mortality, it significantly increases treatment costs. According to the UK’s NHSNational Intelligence Network, a case of ovarian cancer detected early costs an average of £5,000 to treat, whereas one detected late at stage three or four costs £15,000. Similarly, a colon cancer patient detected early typically costs £3,000, while one not identified until a later stage would cost some £13,000.

Traditional tissue biopsies

Currently, oncologists look to pathologists for assistance in tumor diagnosis. Indeed, oncologists cannot proceed with therapy without a tissue diagnosis, nor are they able to discuss prognosis with the patient. After detecting a tumor through a physical examination or imaging, doctors use traditional tissue biopsies to gather information on the attributes of a patient’s cancer.

These pinpoint a cancer’s mutations and malignancy, but solid tissue biopsies are not always straightforward. While some cancers are easily accessed, others are hidden deep inside the body or buried in critical organs. Beyond the physical challenge, sampling from such tumors can be dangerous to patients, and once achieved, they do not always inform on current tumor dynamics. Further, traditional solid tissue biopsies are costly and time consuming to perform; they can yield insufficient tissue to obtain a good understanding of the tumor, and they can be hampered by a patient’s comorbidities, and lack of compliance.

Two significant studies

Although solid tumor tissue is still the gold standard source for clinical molecular analyses, cancer-derived material circulating in the bloodstream has become an appealing alternative showing potential to overcome some of the challenges of solid tissue biopsies.

Findings of two significant studies of liquid biopsies published in 2017 promise a more effective and patient-friendly method for diagnosing cancer: one in the journal Genome Biology, and the other in the journal Nature Genetics. Both studies are on the cusp of developing the world’s first simple blood test, which can both detect early stage cancer, and identify where in the body the cancer is located..

The Genome Biology study

​The study, reported in Genome Biology, describes findings of a blood test, referred to as the CancerLocator, which has been developed by Jasmine Zhou, Professor of Biological and Computer Sciences and her team at the University of California, Los Angeles (UCLA). The Locator detected early stage cancer in 80% of breast, lung and liver cases.

Zhou and her colleagues devised a computer program that uses genetic data to detect circulating tumor DNA (ctDNA) in blood samples. Once identified, the ctDNA is compared to a database of genetic information from hundreds of people to identify where the tumor is located. Zhou’s team discovered that tumors, which arise in different parts of the body, have different signatures, which a computer can spot. “The technology is in its infancy and requires further validation, but the potential benefits to patients are huge . . . . . Non-invasive diagnosis of cancer is important, as it allows the early detection of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease,” says Zhou.

The Nature Genetics study

Researchers led by Kun Zhang, Professor of Bioengineering at the University of California, San Diego (UCSD), are responsible for the study published in the journal Nature Genetics. Zhang developed a test that examined ctDNA in blood from cancer patients and, like Zhou, discovered that not only could it detect cancer early, but could also locate where the tumor is growing in the body. When a tumor starts to take over a part of the body, it competes with normal cells for nutrients and space, killing them off in the process. As normal cells die, they release their DNA into the bloodstream; and that DNA can identify the affected tissue.

“There aremany technical differences on how each approach works . . . The work by the UCLA group is a computer program that uses data published previously by other groups, and has reduced the cancer detection error from roughly 60% to 26.5%. In contrast, we developed a new theoretical framework, generated our own data from over 100 patients and healthy people, and our accuracy of locating cancer in an organ is around 90%,” says Zhang, but he adds, “Major medical challenges don’t get solved by one team working alone”.

Confluence and advances in computing and biology

The research endeavors of Professors Zhou and Zhang have been made possible by the confluence and advances in computing and molecular biology. Over the past 20 years, there has been a paradigm shift in biology, a substantial increase in computing power, huge advances in artificial intelligence (AI), and the costs of data storage have plummeted. It took 13 years, US$3bn, and help from 7 governments to produce the first map of the human genome, which was completed in 2003. Soon it will be possible to sequence an entire genome in less than an hour for US$100.

The end of traditional in vitro diagnostics

Liquid biopsies are a sequencing-based technology used to detect microscopic fragments of DNA in just a few drops of blood, and hold out the potential to diagnose cancers before the onset of symptoms. Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry for his work in understanding how DNA is converted into RNA, “which gives a voice to genetic information that, on its own, is silent,” describes how advances in molecular science are fueling the replacement of traditional in vitro diagnostics with virtually instantaneous, point-of-care diagnostics without resort to complex processes or elaborate and expensive infrastructure. Liquid biopsies, such as those developed by Zhou and Zhang, have the potential to provide clinicians with a rapid and cheap means to detect cancer early, thereby enabling immediate treatment closely tailored to each patient’s disease state.

The clinical implementations of such a test are not widespread, and there has been no regulatory approval of liquid biopsies for diagnosing cancer generally. Notwithstanding, ctDNA is now being extensively studied, as it is a non-invasive “real-time” biomarker that can provide diagnostic and prognostic information before and during treatment; and at progression.

cfDNA and ctDNA

Cell-free DNA (cfDNA) is a broad term that describes DNA, which is freely circulating in the bloodstream, but does not necessarily originate from a tumor. Circulating tumor DNA (ctDNA) is fragmented DNA, which is derived directly from a tumor or from circulating tumor cells (CTCs).

Commercialization of the liquid biopsy race

Bill Gates, Jeff Bezos and leading venture capitalists have poured hundreds of millions into the goal of developing liquid biopsies. The US market alone is projected at US$29bn, according to a 2015 report from investment bank Piper Jaffray. Currently, there are about 40 companies in the US analyzing blood for fragments of DNA shed by dying cancer cells. Notwithstanding, only a few companies have successfully marketed liquid biopsies, and these are limited to identifying the best treatments for certain cancers, and to update treatments as the cancer mutates. So far, no one has been successful in diagnosing incipient cancer from a vial of blood drawn from a patient who looks and feels perfectly healthy.

Some US companies in the liquid biopsy race

At the 2016 meeting of the American Society of Clinical Oncology (ASCO), a Silicon Valley start-up, Guardant Health, which has raised some US$200m, presented findings from a large study involving over 15,000 participants, which demonstrated the accuracy of its liquid biopsy test, Guardant360, for patients with advanced solid tumors. The study found the same patterns of genomic changes in cfDNA reported by the Guardant360 test as those found in 398 patients with matching tissue samples between 94% and 100% of the time.

The 70-gene test is the first comprehensive, non-invasive genomic cancer-sequencing test to market, and according to the company, about 2,000 physicians worldwide have used it. Guardant expects to continue to develop its technology, and maintain a commercial lead in the cfDNA liquid biopsy space. The next step for Guardant is to go beyond sequencing, which matches patients to targeted oncology drugs to the early detection of cancer itself.

Also in 2016 Gates and Bezos teamed up with San Diego's Illumina, which makes most of the DNA sequencing machines that pick appropriate treatments for cancer patients, to launch another liquid biopsy start-up called Grail. In 2017, Grail raised US$900m to help it develop blood-based diagnostics to enable routine, early detection of cancer. The company aims to refine and validate its liquid biopsy technology by running a number of large-scale clinical studies where it expects to sequence hundreds of thousands of patients. Another Californian-based biotech start-up, Freemome, raised US$65m to validate its liquid biopsy technology for the early detection of cancer.

Takeaways

Despite findings of the two 2017 studies reported in the journals Genome Biology and Nature genetics, FDA approval of Roche’s liquid biopsy, massive increase in investment, and significant commercial biotech activity, there is a gap between reality and aspirations for liquid biopsies. To provide doctors with a reliable, point-of-care means to detect cancer early, liquid biopsies will have to overcome several significant challenges. The major one is assay sensitivity and specificity for analysis of ctDNA and cfDNA. To compete with the gold standard solid tissue biopsy, and to ensure that patients receive early diagnosis and appropriate treatment, a successful liquid biopsy assay will have to demonstrate a high positive predictive value. Concomitantly, good sensitivity and excellent specificity will be required to yield acceptable rates of false positives and false negatives. Notwithstanding, the race among bioengineers to develop a non-invasive “real-time” liquid biopsy to detect cancer early is gaining momentum.

Directory:

Tags:

Tobacco is a legacy recreational drug that causes cancers, and kills over 6m people each year

No new food, drink, recreational or over the counter drug with a similar adverse health profile would ever be approved in the modern world

Smoking causes 150 extra mutations in every lung cell

New research demonstrates that smoking causes cancers in organs not exposed to smoke such as the bladder, kidney and pancreas

Smoking triggers cell mutations that can cause cancer years after quitting

Anti-smoking campaigns have decreased the prevalence of smoking, but incidence rates have increased because of population growth

Identifying all the cancer genes will eventually improve treatments

Smoking is playing Russian roulette with your life

Tobacco is the only legal drug that kills millions when used exactly as intended by manufacturers. New research into the root causes of cancer demonstrates how tobacco smoke mutates DNA, and gives rise to more than 17 types of cancers, and surprisingly, causes cancers in organs not directly exposed to tobacco smoke.

Cell mutation and the body’s natural resistance

A mutation occurs when a DNA gene is damaged or changed in such a way as to alter the genetic message carried by that gene. The more mutations a cell acquires, the more likely it is to turn cancerous.

Decreased prevalence, but increased incidence of smoking

Globally, smoking prevalence - the percentage of the population that smokes regularly - has decreased, but the number of cigarette smokers worldwide has increased due to population growth. Today, over 1bn people worldwide smoke tobacco, which each year causes nearly 6m early deaths, many different cancers, pain, misery and grief; not to mention the huge costs to healthcare systems and the loss of productivity. If current trends continue tobacco use will cause more than 8m deaths annually by 2030. On average, smokers die 10 years earlier than nonsmokers.

Cancer and the body’s natural resistance

Cancer is a condition where cells in a specific part of the body mutate and reproduce uncontrollably. There are over 200 different types of cancer. Cancerous cells can invade and destroy surrounding healthy tissue and organs. Cancer sometimes begins in one part of the body before spreading to other areas. This process is known a metastasis. The body has a capacity to naturally resist cancer, through tumor suppressor genes, which function to restrain inappropriate mutations, and stimulate cell death to keep our cells in proper balance.New therapies that boost the body’s own immune system to fight cancer are believed to be a game-changer in cancer treatment.

Cancer and the causes of cancer

Whitfield Growdon, a surgical oncologists from Harvard University Medical School and the Massachusetts General Hospital in Boston, describes cancer and the causes of cancer:

What is cancer?

What causes cancer?

Epidemiology of smoking

Today, it is widely accepted that tobacco use is the single most important preventable health risk in the developed world, and an important cause of premature death worldwide. The research of the British epidemiologists Richard Doll and Tony Bradford Hill, more than anyone else, is responsible for the link between tobacco use and lung cancer. Following reports of several case-controlled studies in the early 1950’s Doll and Hill published findings of a larger case-controlled study in 1954 in the British Medical Journal, which suggested that smoking was, "a cause, and an important cause" of lung cancer. This was followed by the publication of further research findings in 1956. Doll and Hill’s latter study confirmed their earlier case-controlled findings: that there is a higher mortality rate among smokers than in non-smokers, and a clear dose-response relationship between the quantity of tobacco used, and the death rate from lung cancer. Data also indicated a significant progressive reduction in mortality rates with the length of time following the cessation of smoking.

US Surgeon General Report of smoking and lung cancer

The research of Doll and Hill, along with other cohort studies published in the 1950s, formed the basis for the game-changing 1964 report of the US Surgeon General, which concluded that, "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors". This led to groundbreaking research on tobacco use, and investments by governments and nonprofit organizations to reduce tobacco prevalence and cigarette consumption, which in some developed countries has been successful. In 2003, the Framework Convention on Tobacco Control was adopted by the World Health Organization, and has since been ratified by 180 countries.

The best and the worst countries for smoking related lung cancer

Between 1980 and 2012 age-standardized smoking prevalence decreased by 42% for women and 25% for men worldwide. Canada, Iceland, Mexico, and Norway have reduced smoking by more than half in both men and women since 1980. The greatest health risks for both men and women are likely to occur in countries where smoking is pervasive and where smokers consume a large quantity of cigarettes. These countries include China, Ireland, Italy, Japan, Kuwait, South Korea, the Philippines, Uruguay, Switzerland, and several countries in Eastern Europe. The number of cigarettes smoked worldwide has grown to more than 6 trillion. In 75 countries: smokers consume an average of more than 20 cigarettes a day.

Smoking-related deaths in the UK and US

19% (10m) of adults in the UK, and 17% (40m), of adults in the US are current cigarette smokers, a figure, which has more than halved since the mid 1970s. Results from a 50-year study shows that half to two thirds of all lifelong cigarette smokers will be eventually killed by their habit. Death is usually due to lung cancer, chronic obstructive lung disease and coronary heart disease. Many who suffer from these diseases experience years of ill health and subsequent loss of productivity. Every year, around 96,000 people in the UK, and 480,000 people in the US, die from diseases caused by smoking. This equates to 226 and 1,300 smoking-related deaths every day in the UK and US respectively.

Costs

In addition to death and sickness, tobacco use also imposes a significant economic burden on society. These include direct medical costs of treating tobacco-induced illnesses, indirect costs including loss of productivity, fire damage and environmental harm from cigarette litter and destructive farming practices. Cigarettes sales contribute significant tax revenues to national coffers; the industry employs tens of thousands of people who also pay taxes. Notwithstanding, the total burden caused by tobacco products outweighs any economic benefit from their manufacture and sale.

Direct link between the number of cigarettes smoked and cancers

Scientists from the Wellcome Trust Sanger Institute near Cambridge, UK, the Los Alamos National Laboratory in New Mexico, and others have discovered a direct link between the number of cigarettes smoked and the number of mutations in the tumor DNA, and that smoking also causes cancers in organs not exposed to tobacco smoke.

Research published in the Journal Science in 2016 analyzed more than 5,000 cancer tumors from smokers and nonsmokers, and concluded that if you smoke even a few cigarettes a day you will erode the genetic material of most of the cells in your body, and thereby be at a significantly greater risk of cancer. "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking," says Ludmil Alexandrov, a theoretical biologist at Los Alamos National Labroratory and an author of the study.

The discovery means that people who smoke a pack of cigarettes a day for a year, develop on average, 150 extra mutations in every lung cell, and nearly 100 more mutations than usual in each cell of the voice box, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver.

Smoking causes cancers not exposed to smoke

Scientists were surprised to find that tobacco smoke caused mutations in tissues that are not directly exposed to smoke. While more than 70 of the 7,000 chemicals in tobacco smoke have long been known to raise the risk of at least 17 forms of cancer, the precise molecular mechanisms through which these chemicals mutate DNA, and give rise to tumours in different tissues have never been altogether clear, until now. The study showed that some chemicals from tobacco smoke damage DNA directly, but others found their way to different organs and tissues, and ramp up the natural speed at which mutations built up in the tissues in more subtle ways, often by disrupting the way cells function. The more mutations a cell acquires, the more likely it is to turn cancerous.

Why some smokers get cancer and others do not

“It won’t happen to me. . . . My grandfather started smoking when he was 11, smoked 20 a day, and lived ‘til he was 90”. We have all heard this before. But we now know why some smokers get cancer and others do not. it is because of the way mutations arise. When a person smokes, the chemicals they inhale create mutations at random points in the genome. Many of these changes will be harmless, but others will not be so benign. The more smoke a person is exposed to, the greater the chance that the accumulating mutations will hit specific spots in the DNA that turn cells cancerous. Even decades after people stop smoking, former smokers are at a long-term increased risk of developing cancers.“You can really think of it as playing Russian roulette,” says Alexandrov.

Takeaways

Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that do not come into direct contact with smoke.

Sir Mark Walport, director of the Wellcome Trust, says that the findings from the research described above: “will feed into knowledge, methods and practice in patient care.” Dr Peter Campbell, from the Wellcome Trust Sanger Institute says: “The knowledge we extract over the next few years will have major implications for treatment. By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes, and work out which patients will benefit from these novel treatments.”